SAN DIEGO – Adding low doses of gemtuzumab to standard chemotherapy extends survival in de novo acute myeloid leukemia without the toxicity that triggered the monoclonal antibody to be taken off the market in the United States last year, a study has shown.

Median event-free survival among 280 patients, aged 50-70 years, was increased from 11.9 months with standard daunorubicin (Cerubidine) and cytarabine (Ara-C) chemotherapy to 19.6 months with the addition of gemtuzumab ozogamicin (Mylotarg).

The 2-year estimate of event-free survival was 16.5% vs. 41.1% (log-rank P value = .00018; hazard ratio, 0.57).

This translated into an increase in median overall survival from 19.2 months to 34 months with the addition of gemtuzumab, Dr. Sylvie Castaigne reported on behalf of the Acute Leukemia French Association (ALFA) at the annual meeting of the American Society of Hematology. The 2-year overall survival estimate was 43.5% vs. 53.1% (log rank P = .046; HR, 0.70).

Notably, this improvement in survival was not present in patients with unfavorable cytogenetics, comprising 23% of the gemtuzumab group.

At the urging of the U.S. Food and Drug Administration, Pfizer voluntarily withdrew gemtuzumab from the market in June 2010, because of concerns about its toxicity and lack of clinical benefit in patients with acute myeloid leukemia (AML).

The drug remains available in Europe on a compassionate basis for relapsed AML, but not in the frontline setting, according to Dr. Castaigne, professor of hematology at Hôpital de Versailles (France).

When asked during a press briefing whether the current data could resurrect gemtuzumab in the United States or be parlayed into a new indication in Europe, she said, "I think many physicians will ask Pfizer to get the drug on the market."

Dr. Armand Keating, ASH president-elect, who moderated the presentation of the study, said in an interview that "I think it has the potential to change practice, but my concern is that there may be more side effects than are being reported in this particular study and certainly there were previous reports of veno-occlusive disease."

Dr. Castaigne reported three episodes of veno-occlusive disease, two of which were fatal. Prolonged grade 3 or greater thrombocytopenia occurred in 19 patients.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York City, agreed that the data are impressive, but also expressed concern about the veno-occlusive disease events.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No," he said in an interview. "Does it change standard of care? No.

"It is impressive, but I think we need more studies."

Still, Dr. Tallman said that he would advise Pfizer to bring gemtuzumab back on the market for clinical trials, and that a Pfizer executive told him during the presentation that Pfizer would see what it could do.

Dr. Keating, director of hematology at the University of Toronto, said the new data might lead to a consideration of putting gemtuzumab back on the market. "I think it would be very reasonable," he added.

Only 13,000 new patients are diagnosed each year in the United States with AML, but there are 9,000 deaths. Overall survival has improved among younger adults, but there is no evidence of improvement among older adults in 4 decades of investigation, Dr. Castaigne said.

The ALFA group opted to pursue gemtuzumab in AML based on phase I data suggesting that repeated lower-dose infusions would reduce the toxicity associated with the previous 9-mg/m² dose given on days 1 and 14, while enhancing the efficacy of gemtuzumab.

From January 2008 to November 2010, 280 patients were randomized to chemotherapy with daunorubicin 60 mg/m² on days 1-3 and cytarabine 200 mg/m² on days 1-7 with or without gemtuzumab 3 mg/m² on days 1, 4 and 7. Two patients withdrew consent, and were excluded from the analysis. Their median age was 62 years.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No."

If bone marrow blasts were more than 10% at day 15, a second course of daunorubicin 60 mg/m² on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1-3 was given.

Two rounds of consolidation chemotherapy were given to patients who experienced a complete response.

Median relapse-free survival among complete responders was 12.5 months in the control group and 28.1 months in the gemtuzumab group, with 21.7% vs. 50.8% alive at 2 years (log-rank P value = .00029; HR, 0.51), Dr. Castaigne said.

The rate of fatal events possibly related to treatment was similar at 6.7% in the chemotherapy group and 8.7% in the gemtuzumab group, she said.

The incidence of grade 3-4 sepsis was similar at 16% with chemotherapy and 20% with gemtuzumab, as was the rate of ICU admission (12% vs. 14%).

Additional data at the meeting also show a significant survival benefit with gemtuzumab among 806 older patients, with a median age of 67 years, according to Dr. Alan Burnett, head of hematology at Cardiff (Wales) University. Median overall survival increased from 39% to 47% with the addition of gemtuzumab to chemotherapy (P = .02). A lower benefit was observed in those with adverse cytogenetics or secondary disease, according to the study.

Dr. Castaigne reported financial relationships with Pfizer/Wyeth. Dr. Burnett reported financial relationships with Pfizer. Dr. Tallman reported consulting for Genzyme Oncology.

SAN DIEGO – Adding low doses of gemtuzumab to standard chemotherapy extends survival in de novo acute myeloid leukemia without the toxicity that triggered the monoclonal antibody to be taken off the market in the United States last year, a study has shown.

Median event-free survival among 280 patients, aged 50-70 years, was increased from 11.9 months with standard daunorubicin (Cerubidine) and cytarabine (Ara-C) chemotherapy to 19.6 months with the addition of gemtuzumab ozogamicin (Mylotarg).

The 2-year estimate of event-free survival was 16.5% vs. 41.1% (log-rank P value = .00018; hazard ratio, 0.57).

This translated into an increase in median overall survival from 19.2 months to 34 months with the addition of gemtuzumab, Dr. Sylvie Castaigne reported on behalf of the Acute Leukemia French Association (ALFA) at the annual meeting of the American Society of Hematology. The 2-year overall survival estimate was 43.5% vs. 53.1% (log rank P = .046; HR, 0.70).

Notably, this improvement in survival was not present in patients with unfavorable cytogenetics, comprising 23% of the gemtuzumab group.

At the urging of the U.S. Food and Drug Administration, Pfizer voluntarily withdrew gemtuzumab from the market in June 2010, because of concerns about its toxicity and lack of clinical benefit in patients with acute myeloid leukemia (AML).

The drug remains available in Europe on a compassionate basis for relapsed AML, but not in the frontline setting, according to Dr. Castaigne, professor of hematology at Hôpital de Versailles (France).

When asked during a press briefing whether the current data could resurrect gemtuzumab in the United States or be parlayed into a new indication in Europe, she said, "I think many physicians will ask Pfizer to get the drug on the market."

Dr. Armand Keating, ASH president-elect, who moderated the presentation of the study, said in an interview that "I think it has the potential to change practice, but my concern is that there may be more side effects than are being reported in this particular study and certainly there were previous reports of veno-occlusive disease."

Dr. Castaigne reported three episodes of veno-occlusive disease, two of which were fatal. Prolonged grade 3 or greater thrombocytopenia occurred in 19 patients.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York City, agreed that the data are impressive, but also expressed concern about the veno-occlusive disease events.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No," he said in an interview. "Does it change standard of care? No.

"It is impressive, but I think we need more studies."

Still, Dr. Tallman said that he would advise Pfizer to bring gemtuzumab back on the market for clinical trials, and that a Pfizer executive told him during the presentation that Pfizer would see what it could do.

Dr. Keating, director of hematology at the University of Toronto, said the new data might lead to a consideration of putting gemtuzumab back on the market. "I think it would be very reasonable," he added.

Only 13,000 new patients are diagnosed each year in the United States with AML, but there are 9,000 deaths. Overall survival has improved among younger adults, but there is no evidence of improvement among older adults in 4 decades of investigation, Dr. Castaigne said.

The ALFA group opted to pursue gemtuzumab in AML based on phase I data suggesting that repeated lower-dose infusions would reduce the toxicity associated with the previous 9-mg/m² dose given on days 1 and 14, while enhancing the efficacy of gemtuzumab.

From January 2008 to November 2010, 280 patients were randomized to chemotherapy with daunorubicin 60 mg/m² on days 1-3 and cytarabine 200 mg/m² on days 1-7 with or without gemtuzumab 3 mg/m² on days 1, 4 and 7. Two patients withdrew consent, and were excluded from the analysis. Their median age was 62 years.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No."

If bone marrow blasts were more than 10% at day 15, a second course of daunorubicin 60 mg/m² on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1-3 was given.

Two rounds of consolidation chemotherapy were given to patients who experienced a complete response.

Median relapse-free survival among complete responders was 12.5 months in the control group and 28.1 months in the gemtuzumab group, with 21.7% vs. 50.8% alive at 2 years (log-rank P value = .00029; HR, 0.51), Dr. Castaigne said.

The rate of fatal events possibly related to treatment was similar at 6.7% in the chemotherapy group and 8.7% in the gemtuzumab group, she said.

The incidence of grade 3-4 sepsis was similar at 16% with chemotherapy and 20% with gemtuzumab, as was the rate of ICU admission (12% vs. 14%).

Additional data at the meeting also show a significant survival benefit with gemtuzumab among 806 older patients, with a median age of 67 years, according to Dr. Alan Burnett, head of hematology at Cardiff (Wales) University. Median overall survival increased from 39% to 47% with the addition of gemtuzumab to chemotherapy (P = .02). A lower benefit was observed in those with adverse cytogenetics or secondary disease, according to the study.

Dr. Castaigne reported financial relationships with Pfizer/Wyeth. Dr. Burnett reported financial relationships with Pfizer. Dr. Tallman reported consulting for Genzyme Oncology.

SAN DIEGO – Adding low doses of gemtuzumab to standard chemotherapy extends survival in de novo acute myeloid leukemia without the toxicity that triggered the monoclonal antibody to be taken off the market in the United States last year, a study has shown.

Median event-free survival among 280 patients, aged 50-70 years, was increased from 11.9 months with standard daunorubicin (Cerubidine) and cytarabine (Ara-C) chemotherapy to 19.6 months with the addition of gemtuzumab ozogamicin (Mylotarg).

The 2-year estimate of event-free survival was 16.5% vs. 41.1% (log-rank P value = .00018; hazard ratio, 0.57).

This translated into an increase in median overall survival from 19.2 months to 34 months with the addition of gemtuzumab, Dr. Sylvie Castaigne reported on behalf of the Acute Leukemia French Association (ALFA) at the annual meeting of the American Society of Hematology. The 2-year overall survival estimate was 43.5% vs. 53.1% (log rank P = .046; HR, 0.70).

Notably, this improvement in survival was not present in patients with unfavorable cytogenetics, comprising 23% of the gemtuzumab group.

At the urging of the U.S. Food and Drug Administration, Pfizer voluntarily withdrew gemtuzumab from the market in June 2010, because of concerns about its toxicity and lack of clinical benefit in patients with acute myeloid leukemia (AML).

The drug remains available in Europe on a compassionate basis for relapsed AML, but not in the frontline setting, according to Dr. Castaigne, professor of hematology at Hôpital de Versailles (France).

When asked during a press briefing whether the current data could resurrect gemtuzumab in the United States or be parlayed into a new indication in Europe, she said, "I think many physicians will ask Pfizer to get the drug on the market."

Dr. Armand Keating, ASH president-elect, who moderated the presentation of the study, said in an interview that "I think it has the potential to change practice, but my concern is that there may be more side effects than are being reported in this particular study and certainly there were previous reports of veno-occlusive disease."

Dr. Castaigne reported three episodes of veno-occlusive disease, two of which were fatal. Prolonged grade 3 or greater thrombocytopenia occurred in 19 patients.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York City, agreed that the data are impressive, but also expressed concern about the veno-occlusive disease events.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No," he said in an interview. "Does it change standard of care? No.

"It is impressive, but I think we need more studies."

Still, Dr. Tallman said that he would advise Pfizer to bring gemtuzumab back on the market for clinical trials, and that a Pfizer executive told him during the presentation that Pfizer would see what it could do.

Dr. Keating, director of hematology at the University of Toronto, said the new data might lead to a consideration of putting gemtuzumab back on the market. "I think it would be very reasonable," he added.

Only 13,000 new patients are diagnosed each year in the United States with AML, but there are 9,000 deaths. Overall survival has improved among younger adults, but there is no evidence of improvement among older adults in 4 decades of investigation, Dr. Castaigne said.

The ALFA group opted to pursue gemtuzumab in AML based on phase I data suggesting that repeated lower-dose infusions would reduce the toxicity associated with the previous 9-mg/m² dose given on days 1 and 14, while enhancing the efficacy of gemtuzumab.

From January 2008 to November 2010, 280 patients were randomized to chemotherapy with daunorubicin 60 mg/m² on days 1-3 and cytarabine 200 mg/m² on days 1-7 with or without gemtuzumab 3 mg/m² on days 1, 4 and 7. Two patients withdrew consent, and were excluded from the analysis. Their median age was 62 years.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No."

If bone marrow blasts were more than 10% at day 15, a second course of daunorubicin 60 mg/m² on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1-3 was given.

Two rounds of consolidation chemotherapy were given to patients who experienced a complete response.

Median relapse-free survival among complete responders was 12.5 months in the control group and 28.1 months in the gemtuzumab group, with 21.7% vs. 50.8% alive at 2 years (log-rank P value = .00029; HR, 0.51), Dr. Castaigne said.

The rate of fatal events possibly related to treatment was similar at 6.7% in the chemotherapy group and 8.7% in the gemtuzumab group, she said.

The incidence of grade 3-4 sepsis was similar at 16% with chemotherapy and 20% with gemtuzumab, as was the rate of ICU admission (12% vs. 14%).

Additional data at the meeting also show a significant survival benefit with gemtuzumab among 806 older patients, with a median age of 67 years, according to Dr. Alan Burnett, head of hematology at Cardiff (Wales) University. Median overall survival increased from 39% to 47% with the addition of gemtuzumab to chemotherapy (P = .02). A lower benefit was observed in those with adverse cytogenetics or secondary disease, according to the study.

Dr. Castaigne reported financial relationships with Pfizer/Wyeth. Dr. Burnett reported financial relationships with Pfizer. Dr. Tallman reported consulting for Genzyme Oncology.

Researchers using massively parallel sequencing to characterize the spectrum of somatic mutations in chronic lymphocytic leukemia identified nine genes that are mutated at significant frequencies in the disease.

Of these nine "driver" genes, which were identified from DNA samples from normal tissues and tumors in 91 patients with chronic lymphocytic leukemia, four have previously established roles in the disease (TP53, ATM, MYD88, and NOTCH1), and five do not (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X), Dr. Lili Wang of the Dana-Farber Cancer Institute, Boston, and her colleagues reported online in the Dec. 12 issue of the New England Journal of Medicine. The findings were reported simultaneously at the annual meeting of the American Society of Hematology.

"Strikingly, the second most frequently mutated gene in our cohort was splicing factor 3b, subunit 1 (SF3B1), with missense mutations occurring in 14 of 91 patients (15%). SF3B1 is a component of the SF3B complex, which is associated with the U2 small nuclear ribonucleoprotein (snRNP), at the catalytic center of the spliceosome," the investigators said (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMoa1109016]).

The nine driver genes identified in this study appear in five core signaling pathways, and the genes each play different, though well-established roles in these pathways, such as DNA repair and cell-cycle control, Notch signaling, inflammatory pathways, and RNA splicing (in which SF3B1, in particular, was implicated). Furthermore, each driver mutation was found to be associated with different key abnormalities; for example, the findings indicate there may be an interaction between del(11q), which is associated with aggressive disease, and SF3B1 mutation in the pathogenesis of a clinical subgroup of chronic lymphocytic leukemia.

Overall, the investigators concluded that:

• Chronic lymphocytic leukemia has a lower rate of somatic mutation than most solid tumors.

• The rate of nonsynonymous mutation was not strongly affected by therapy.

• In addition to the expected mutations in cell-cycle and DNA-repair pathways, genetic alterations in Notch signaling, inflammatory pathways, and RNA splicing and processing also exist.

• Driver mutations showed striking associations with standard prognostic markers.

The latter suggests that "particular combinations of genetic alterations may act in concert to drive cancer," the investigators said.

The findings regarding the core spliceosome component SF3B1, which they described as a "major surprise," led to further analyses that suggested that SF3B1 mutations lead to "mistakes in the splicing of ... transcripts that affect the pathogenesis of chronic lymphocytic leukemia," they said, adding that ongoing studies will evaluate how mutations in SF3B1 alter its function in the processing of critical messenger RNAs.

The study, and in particular the findings regarding SF3B1 mutations, illustrate how identification of coding mutations in chronic lymphocytic leukemia can lead to the development of mechanistic hypotheses, novel prognostic markers, and potential therapeutic targets, Dr. Wang and her associates said.

They also noted the information provides a starting point for determining "which genes within chromosomal deletions and amplifications are essential, how each mutation alters cellular networks and phenotypes, which combinations of mutations are critical in the development of cancer, and how genetic events in the host may affect the importance of specific mutations and their combinations."

In an accompanying editorial, Dr. Benjamin Ebert and Olivier A. Bernard, Ph.D., commented that the study finding regarding mutations in genes involved in RNA splicing, although highly unexpected, converge remarkably with recent published findings from studies of myelodysplastic syndromes (N. Engl. J. Med. 2011;35:1384-95; Nature 2011;478:64-9).

SF3B1 mutations were found in 20% of patients with myelodysplastic syndromes, and in 65% of patients with refractory anemia and ring sideroblasts in one study (N. Engl. J. Med. 2011;35:1384-95).

"Moreover, mutations have been reported in multiple components of the spliceosome in 45%-85% of patients with myelodysplastic syndrome. SF3B1 mutations also occur in 1%-5% of samples from a wide range of tumor types, which indicates that mutations in RNA splicing factors are a widespread cause of oncogenic transformation," they added.

These and other findings, taken together, raise the "provocative possibility" that SF3B1 mutations may sometimes occur first in hematopoietic stem cells, with "additional mutations then being acquired in either the lymphoid or the myeloid lineages and causing chronic lymphocytic leukemia or myelodysplastic syndromes, respectively," Dr. Ebert of Brigham and Women’s Hospital, Boston, and Dr. Bernard, who is with INSERM at Institut Gustave Roussy, Villejuif, France, wrote (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMe1111584]).

The findings have implications for determining prognosis, and for identifying targets for treatment. For example, the identification of mutations in genes encoding the RNA splicing machinery raises the possibility that spliceosome could be a therapeutic target, they said.

This study was supported by grants from the National Institutes of Health, the National Cancer Institute, the Melton and Rosenbach Funds, the Blavatnik Family Foundation, the Howard Hughes Medical Institute (via an Early Career Physician-Scientist Award), and the Damon Runyon Cancer Research Foundation. Dr. Wang said she had no relevant financial disclosures. Some of the coauthors said they were consultants to numerous pharmaceutical companies or owned stock in pharmaceutical companies. Other than employment by INSERM on the part of Dr. Bernard, neither he nor Dr. Ebert had any relevant financial disclosures to report.

Researchers using massively parallel sequencing to characterize the spectrum of somatic mutations in chronic lymphocytic leukemia identified nine genes that are mutated at significant frequencies in the disease.

Of these nine "driver" genes, which were identified from DNA samples from normal tissues and tumors in 91 patients with chronic lymphocytic leukemia, four have previously established roles in the disease (TP53, ATM, MYD88, and NOTCH1), and five do not (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X), Dr. Lili Wang of the Dana-Farber Cancer Institute, Boston, and her colleagues reported online in the Dec. 12 issue of the New England Journal of Medicine. The findings were reported simultaneously at the annual meeting of the American Society of Hematology.

"Strikingly, the second most frequently mutated gene in our cohort was splicing factor 3b, subunit 1 (SF3B1), with missense mutations occurring in 14 of 91 patients (15%). SF3B1 is a component of the SF3B complex, which is associated with the U2 small nuclear ribonucleoprotein (snRNP), at the catalytic center of the spliceosome," the investigators said (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMoa1109016]).

The nine driver genes identified in this study appear in five core signaling pathways, and the genes each play different, though well-established roles in these pathways, such as DNA repair and cell-cycle control, Notch signaling, inflammatory pathways, and RNA splicing (in which SF3B1, in particular, was implicated). Furthermore, each driver mutation was found to be associated with different key abnormalities; for example, the findings indicate there may be an interaction between del(11q), which is associated with aggressive disease, and SF3B1 mutation in the pathogenesis of a clinical subgroup of chronic lymphocytic leukemia.

Overall, the investigators concluded that:

• Chronic lymphocytic leukemia has a lower rate of somatic mutation than most solid tumors.

• The rate of nonsynonymous mutation was not strongly affected by therapy.

• In addition to the expected mutations in cell-cycle and DNA-repair pathways, genetic alterations in Notch signaling, inflammatory pathways, and RNA splicing and processing also exist.

• Driver mutations showed striking associations with standard prognostic markers.

The latter suggests that "particular combinations of genetic alterations may act in concert to drive cancer," the investigators said.

The findings regarding the core spliceosome component SF3B1, which they described as a "major surprise," led to further analyses that suggested that SF3B1 mutations lead to "mistakes in the splicing of ... transcripts that affect the pathogenesis of chronic lymphocytic leukemia," they said, adding that ongoing studies will evaluate how mutations in SF3B1 alter its function in the processing of critical messenger RNAs.

The study, and in particular the findings regarding SF3B1 mutations, illustrate how identification of coding mutations in chronic lymphocytic leukemia can lead to the development of mechanistic hypotheses, novel prognostic markers, and potential therapeutic targets, Dr. Wang and her associates said.

They also noted the information provides a starting point for determining "which genes within chromosomal deletions and amplifications are essential, how each mutation alters cellular networks and phenotypes, which combinations of mutations are critical in the development of cancer, and how genetic events in the host may affect the importance of specific mutations and their combinations."

In an accompanying editorial, Dr. Benjamin Ebert and Olivier A. Bernard, Ph.D., commented that the study finding regarding mutations in genes involved in RNA splicing, although highly unexpected, converge remarkably with recent published findings from studies of myelodysplastic syndromes (N. Engl. J. Med. 2011;35:1384-95; Nature 2011;478:64-9).

SF3B1 mutations were found in 20% of patients with myelodysplastic syndromes, and in 65% of patients with refractory anemia and ring sideroblasts in one study (N. Engl. J. Med. 2011;35:1384-95).

"Moreover, mutations have been reported in multiple components of the spliceosome in 45%-85% of patients with myelodysplastic syndrome. SF3B1 mutations also occur in 1%-5% of samples from a wide range of tumor types, which indicates that mutations in RNA splicing factors are a widespread cause of oncogenic transformation," they added.

These and other findings, taken together, raise the "provocative possibility" that SF3B1 mutations may sometimes occur first in hematopoietic stem cells, with "additional mutations then being acquired in either the lymphoid or the myeloid lineages and causing chronic lymphocytic leukemia or myelodysplastic syndromes, respectively," Dr. Ebert of Brigham and Women’s Hospital, Boston, and Dr. Bernard, who is with INSERM at Institut Gustave Roussy, Villejuif, France, wrote (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMe1111584]).

The findings have implications for determining prognosis, and for identifying targets for treatment. For example, the identification of mutations in genes encoding the RNA splicing machinery raises the possibility that spliceosome could be a therapeutic target, they said.

This study was supported by grants from the National Institutes of Health, the National Cancer Institute, the Melton and Rosenbach Funds, the Blavatnik Family Foundation, the Howard Hughes Medical Institute (via an Early Career Physician-Scientist Award), and the Damon Runyon Cancer Research Foundation. Dr. Wang said she had no relevant financial disclosures. Some of the coauthors said they were consultants to numerous pharmaceutical companies or owned stock in pharmaceutical companies. Other than employment by INSERM on the part of Dr. Bernard, neither he nor Dr. Ebert had any relevant financial disclosures to report.

Researchers using massively parallel sequencing to characterize the spectrum of somatic mutations in chronic lymphocytic leukemia identified nine genes that are mutated at significant frequencies in the disease.

Of these nine "driver" genes, which were identified from DNA samples from normal tissues and tumors in 91 patients with chronic lymphocytic leukemia, four have previously established roles in the disease (TP53, ATM, MYD88, and NOTCH1), and five do not (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X), Dr. Lili Wang of the Dana-Farber Cancer Institute, Boston, and her colleagues reported online in the Dec. 12 issue of the New England Journal of Medicine. The findings were reported simultaneously at the annual meeting of the American Society of Hematology.

"Strikingly, the second most frequently mutated gene in our cohort was splicing factor 3b, subunit 1 (SF3B1), with missense mutations occurring in 14 of 91 patients (15%). SF3B1 is a component of the SF3B complex, which is associated with the U2 small nuclear ribonucleoprotein (snRNP), at the catalytic center of the spliceosome," the investigators said (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMoa1109016]).

The nine driver genes identified in this study appear in five core signaling pathways, and the genes each play different, though well-established roles in these pathways, such as DNA repair and cell-cycle control, Notch signaling, inflammatory pathways, and RNA splicing (in which SF3B1, in particular, was implicated). Furthermore, each driver mutation was found to be associated with different key abnormalities; for example, the findings indicate there may be an interaction between del(11q), which is associated with aggressive disease, and SF3B1 mutation in the pathogenesis of a clinical subgroup of chronic lymphocytic leukemia.

Overall, the investigators concluded that:

• Chronic lymphocytic leukemia has a lower rate of somatic mutation than most solid tumors.

• The rate of nonsynonymous mutation was not strongly affected by therapy.

• In addition to the expected mutations in cell-cycle and DNA-repair pathways, genetic alterations in Notch signaling, inflammatory pathways, and RNA splicing and processing also exist.

• Driver mutations showed striking associations with standard prognostic markers.

The latter suggests that "particular combinations of genetic alterations may act in concert to drive cancer," the investigators said.

The findings regarding the core spliceosome component SF3B1, which they described as a "major surprise," led to further analyses that suggested that SF3B1 mutations lead to "mistakes in the splicing of ... transcripts that affect the pathogenesis of chronic lymphocytic leukemia," they said, adding that ongoing studies will evaluate how mutations in SF3B1 alter its function in the processing of critical messenger RNAs.

The study, and in particular the findings regarding SF3B1 mutations, illustrate how identification of coding mutations in chronic lymphocytic leukemia can lead to the development of mechanistic hypotheses, novel prognostic markers, and potential therapeutic targets, Dr. Wang and her associates said.

They also noted the information provides a starting point for determining "which genes within chromosomal deletions and amplifications are essential, how each mutation alters cellular networks and phenotypes, which combinations of mutations are critical in the development of cancer, and how genetic events in the host may affect the importance of specific mutations and their combinations."

In an accompanying editorial, Dr. Benjamin Ebert and Olivier A. Bernard, Ph.D., commented that the study finding regarding mutations in genes involved in RNA splicing, although highly unexpected, converge remarkably with recent published findings from studies of myelodysplastic syndromes (N. Engl. J. Med. 2011;35:1384-95; Nature 2011;478:64-9).

SF3B1 mutations were found in 20% of patients with myelodysplastic syndromes, and in 65% of patients with refractory anemia and ring sideroblasts in one study (N. Engl. J. Med. 2011;35:1384-95).

"Moreover, mutations have been reported in multiple components of the spliceosome in 45%-85% of patients with myelodysplastic syndrome. SF3B1 mutations also occur in 1%-5% of samples from a wide range of tumor types, which indicates that mutations in RNA splicing factors are a widespread cause of oncogenic transformation," they added.

These and other findings, taken together, raise the "provocative possibility" that SF3B1 mutations may sometimes occur first in hematopoietic stem cells, with "additional mutations then being acquired in either the lymphoid or the myeloid lineages and causing chronic lymphocytic leukemia or myelodysplastic syndromes, respectively," Dr. Ebert of Brigham and Women’s Hospital, Boston, and Dr. Bernard, who is with INSERM at Institut Gustave Roussy, Villejuif, France, wrote (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMe1111584]).

The findings have implications for determining prognosis, and for identifying targets for treatment. For example, the identification of mutations in genes encoding the RNA splicing machinery raises the possibility that spliceosome could be a therapeutic target, they said.

This study was supported by grants from the National Institutes of Health, the National Cancer Institute, the Melton and Rosenbach Funds, the Blavatnik Family Foundation, the Howard Hughes Medical Institute (via an Early Career Physician-Scientist Award), and the Damon Runyon Cancer Research Foundation. Dr. Wang said she had no relevant financial disclosures. Some of the coauthors said they were consultants to numerous pharmaceutical companies or owned stock in pharmaceutical companies. Other than employment by INSERM on the part of Dr. Bernard, neither he nor Dr. Ebert had any relevant financial disclosures to report.

SAN DIEGO – Data mined from several phase II studies of carfilzomib monotherapy confirm previous observations, but also raise new questions and insights into the use of the investigational proteasome inhibitor in relapsed and/or refractory multiple myeloma.

The first of three posters simultaneously presented at the American Society of Hematology used multivariate modeling to confirm a dose-response relationship for carfilzomib in bortezomib (Velcade)-naive and bortezomib-treated patients.

After study effect was adjusted for, the odds of achieving a partial response or better for a patient treated with 27 mg/m² were 4.08-fold higher than for a patient receiving only 20 mg/m² (P less than .001).

When using the average dose as a continuous variable and again adjusting for study effect, the odds of a response increased by 1.28-fold for each 1-mg/m² increase in average carfilzomib dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m² to 27 mg/m² (P less than .001), reported Sunhee Ro, Ph.D., an employee of San Francisco–based Onyx Pharmaceuticals, which is developing the drug. Statistician Pierre Squifflet of the International Drug Development Institute in Belgium was the lead author.

The dose-effect relationship was observed not only on the primary end point of overall response rate, but also time to progression, progression-free survival, and overall survival.

The analysis included three study populations: 266 heavily pretreated patients who had received at least two prior therapies including bortezomib and either thalidomide or lenalidomide and who received carfilzomib 20 mg/m² in cycle one with escalation to 27 mg/m² if tolerable, 35 patients pretreated with one to three prior therapies including bortezomib who received carfilzomib 20 mg/m², and 129 bortezomib-naive patients treated at 20 mg/m² or the same dose with escalation to 27 mg/m² if tolerable.

A corresponding toxicity analysis is underway, as are clinical trials assessing higher-dose regimens. The analysis raises the obvious question of whether the 20- to-27-mg/m² dose schedule Onyx used in its recent accelerated review filing for carfilzomib is possibly too low.

Dr. Ro and other Onyx employees milling about the poster were hesitant to comment, with Ruben Sanchez, the associate director of publications at Onyx, saying only that the maximum tolerated dose of carfilzomib is 20-70 mg/m² and that studies are ongoing at an "experimental dose" of 20-56 mg/m².

Unfavorable Cytogenetics

The second poster confirmed that unfavorable cytogenetics did not significantly impact overall response rates or response duration, but found that median overall survival was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities at 11.9 months vs. 19.2 months.

A similar trend was observed for median progression-free survival at 3.6 months vs. 4.6 months, reported Dr. Andrzej J. Jakubowiak of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

When the researchers looked at specific cytogenetic abnormalities in the 234 evaluable patients dosed using the 20- to 27-mg/m² schedule, median overall survival was the lowest among those with deletion 17p3 at 7 months vs. 10.6 months with deletion 13, 10.4 months with hypodiploidy, and 11.8 months with translocation t(4:14).

 

Progression-free survival and time to progression also tended to be longer for patients with hypoploidy and translocation t(4:14) than for patients with deletion 13 and deletion 17p13. This observation is compatible with current thinking highlighted in an educational multiple myeloma program at the meeting, that cytogenetic abnormalities are becoming something of a moving target, coauthor Dr. Sundar Jagannath, director of the multiple myeloma program at Mt. Sinai Medical Center in New York, said in an interview.

"One area, 17p13 deletion, is still a challenge, but t4;14 translocation, hypodiploidy, and deletion 13 ... are all no longer considered as high risk in the presence of protease inhibitors," he said. "It is nothing unique to carfilzomib; it’s just the class of protease inhibitors."

Dr. Jagannath said that even in patients with the problematic 17p13 deletion, researchers have used gene expression profiling to further delineate those at high and low risk, and that data clearly show that outcomes are improved in low-risk 17p13 deletion patients with the inclusion of the protease inhibitor bortezomib therapy.

Safety Data

The third poster features integrated safety data from 526 heavily pretreated patients receiving carfilzomib 20 mg/m² or 20-27 mg/m², showing that grade 3/4 treatment adverse events occurred in 80% of patients, but were characterized as mostly reversible and primarily hematologic in nature.

The most common grade 3 adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). There were no fatal hematologic events and no grade 4 or 5 bleeding reactions associated with thrombocytopenia, reported Dr. Seema Singhal, professor of medicine and director of the multiple myeloma program at Northwestern Memorial Hospital in Chicago, and her associates.

Cardiac events, some of which resulted in discontinuation or death, occurred. Cardiac failure events were reported in 7% with discontinuation due to heart failure in 2%, cardiac arrest in 1%, and myocardial ischemia in less than 1%.

"The extent to which these [events] were due to patients’ baseline comorbidities, toxicity from prior treatment, effects of multiple myeloma, carfilzomib itself, or a combination of these factors cannot be determined," the authors wrote.

Dr. Jagannath said the cardiac events do not represent a new signal.

The studies in the analyses were supported by Onyx. Dr. Ro is an employee of Onyx. Dr. Jakubowiak, Dr. Singhal, and Dr Jagannath reported financial relationships with several firms including Onyx.

SAN DIEGO – Data mined from several phase II studies of carfilzomib monotherapy confirm previous observations, but also raise new questions and insights into the use of the investigational proteasome inhibitor in relapsed and/or refractory multiple myeloma.

The first of three posters simultaneously presented at the American Society of Hematology used multivariate modeling to confirm a dose-response relationship for carfilzomib in bortezomib (Velcade)-naive and bortezomib-treated patients.

After study effect was adjusted for, the odds of achieving a partial response or better for a patient treated with 27 mg/m² were 4.08-fold higher than for a patient receiving only 20 mg/m² (P less than .001).

When using the average dose as a continuous variable and again adjusting for study effect, the odds of a response increased by 1.28-fold for each 1-mg/m² increase in average carfilzomib dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m² to 27 mg/m² (P less than .001), reported Sunhee Ro, Ph.D., an employee of San Francisco–based Onyx Pharmaceuticals, which is developing the drug. Statistician Pierre Squifflet of the International Drug Development Institute in Belgium was the lead author.

The dose-effect relationship was observed not only on the primary end point of overall response rate, but also time to progression, progression-free survival, and overall survival.

The analysis included three study populations: 266 heavily pretreated patients who had received at least two prior therapies including bortezomib and either thalidomide or lenalidomide and who received carfilzomib 20 mg/m² in cycle one with escalation to 27 mg/m² if tolerable, 35 patients pretreated with one to three prior therapies including bortezomib who received carfilzomib 20 mg/m², and 129 bortezomib-naive patients treated at 20 mg/m² or the same dose with escalation to 27 mg/m² if tolerable.

A corresponding toxicity analysis is underway, as are clinical trials assessing higher-dose regimens. The analysis raises the obvious question of whether the 20- to-27-mg/m² dose schedule Onyx used in its recent accelerated review filing for carfilzomib is possibly too low.

Dr. Ro and other Onyx employees milling about the poster were hesitant to comment, with Ruben Sanchez, the associate director of publications at Onyx, saying only that the maximum tolerated dose of carfilzomib is 20-70 mg/m² and that studies are ongoing at an "experimental dose" of 20-56 mg/m².

Unfavorable Cytogenetics

The second poster confirmed that unfavorable cytogenetics did not significantly impact overall response rates or response duration, but found that median overall survival was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities at 11.9 months vs. 19.2 months.

A similar trend was observed for median progression-free survival at 3.6 months vs. 4.6 months, reported Dr. Andrzej J. Jakubowiak of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

When the researchers looked at specific cytogenetic abnormalities in the 234 evaluable patients dosed using the 20- to 27-mg/m² schedule, median overall survival was the lowest among those with deletion 17p3 at 7 months vs. 10.6 months with deletion 13, 10.4 months with hypodiploidy, and 11.8 months with translocation t(4:14).

 

Progression-free survival and time to progression also tended to be longer for patients with hypoploidy and translocation t(4:14) than for patients with deletion 13 and deletion 17p13. This observation is compatible with current thinking highlighted in an educational multiple myeloma program at the meeting, that cytogenetic abnormalities are becoming something of a moving target, coauthor Dr. Sundar Jagannath, director of the multiple myeloma program at Mt. Sinai Medical Center in New York, said in an interview.

"One area, 17p13 deletion, is still a challenge, but t4;14 translocation, hypodiploidy, and deletion 13 ... are all no longer considered as high risk in the presence of protease inhibitors," he said. "It is nothing unique to carfilzomib; it’s just the class of protease inhibitors."

Dr. Jagannath said that even in patients with the problematic 17p13 deletion, researchers have used gene expression profiling to further delineate those at high and low risk, and that data clearly show that outcomes are improved in low-risk 17p13 deletion patients with the inclusion of the protease inhibitor bortezomib therapy.

Safety Data

The third poster features integrated safety data from 526 heavily pretreated patients receiving carfilzomib 20 mg/m² or 20-27 mg/m², showing that grade 3/4 treatment adverse events occurred in 80% of patients, but were characterized as mostly reversible and primarily hematologic in nature.

The most common grade 3 adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). There were no fatal hematologic events and no grade 4 or 5 bleeding reactions associated with thrombocytopenia, reported Dr. Seema Singhal, professor of medicine and director of the multiple myeloma program at Northwestern Memorial Hospital in Chicago, and her associates.

Cardiac events, some of which resulted in discontinuation or death, occurred. Cardiac failure events were reported in 7% with discontinuation due to heart failure in 2%, cardiac arrest in 1%, and myocardial ischemia in less than 1%.

"The extent to which these [events] were due to patients’ baseline comorbidities, toxicity from prior treatment, effects of multiple myeloma, carfilzomib itself, or a combination of these factors cannot be determined," the authors wrote.

Dr. Jagannath said the cardiac events do not represent a new signal.

The studies in the analyses were supported by Onyx. Dr. Ro is an employee of Onyx. Dr. Jakubowiak, Dr. Singhal, and Dr Jagannath reported financial relationships with several firms including Onyx.

SAN DIEGO – Data mined from several phase II studies of carfilzomib monotherapy confirm previous observations, but also raise new questions and insights into the use of the investigational proteasome inhibitor in relapsed and/or refractory multiple myeloma.

The first of three posters simultaneously presented at the American Society of Hematology used multivariate modeling to confirm a dose-response relationship for carfilzomib in bortezomib (Velcade)-naive and bortezomib-treated patients.

After study effect was adjusted for, the odds of achieving a partial response or better for a patient treated with 27 mg/m² were 4.08-fold higher than for a patient receiving only 20 mg/m² (P less than .001).

When using the average dose as a continuous variable and again adjusting for study effect, the odds of a response increased by 1.28-fold for each 1-mg/m² increase in average carfilzomib dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m² to 27 mg/m² (P less than .001), reported Sunhee Ro, Ph.D., an employee of San Francisco–based Onyx Pharmaceuticals, which is developing the drug. Statistician Pierre Squifflet of the International Drug Development Institute in Belgium was the lead author.

The dose-effect relationship was observed not only on the primary end point of overall response rate, but also time to progression, progression-free survival, and overall survival.

The analysis included three study populations: 266 heavily pretreated patients who had received at least two prior therapies including bortezomib and either thalidomide or lenalidomide and who received carfilzomib 20 mg/m² in cycle one with escalation to 27 mg/m² if tolerable, 35 patients pretreated with one to three prior therapies including bortezomib who received carfilzomib 20 mg/m², and 129 bortezomib-naive patients treated at 20 mg/m² or the same dose with escalation to 27 mg/m² if tolerable.

A corresponding toxicity analysis is underway, as are clinical trials assessing higher-dose regimens. The analysis raises the obvious question of whether the 20- to-27-mg/m² dose schedule Onyx used in its recent accelerated review filing for carfilzomib is possibly too low.

Dr. Ro and other Onyx employees milling about the poster were hesitant to comment, with Ruben Sanchez, the associate director of publications at Onyx, saying only that the maximum tolerated dose of carfilzomib is 20-70 mg/m² and that studies are ongoing at an "experimental dose" of 20-56 mg/m².

Unfavorable Cytogenetics

The second poster confirmed that unfavorable cytogenetics did not significantly impact overall response rates or response duration, but found that median overall survival was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities at 11.9 months vs. 19.2 months.

A similar trend was observed for median progression-free survival at 3.6 months vs. 4.6 months, reported Dr. Andrzej J. Jakubowiak of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

When the researchers looked at specific cytogenetic abnormalities in the 234 evaluable patients dosed using the 20- to 27-mg/m² schedule, median overall survival was the lowest among those with deletion 17p3 at 7 months vs. 10.6 months with deletion 13, 10.4 months with hypodiploidy, and 11.8 months with translocation t(4:14).

 

Progression-free survival and time to progression also tended to be longer for patients with hypoploidy and translocation t(4:14) than for patients with deletion 13 and deletion 17p13. This observation is compatible with current thinking highlighted in an educational multiple myeloma program at the meeting, that cytogenetic abnormalities are becoming something of a moving target, coauthor Dr. Sundar Jagannath, director of the multiple myeloma program at Mt. Sinai Medical Center in New York, said in an interview.

"One area, 17p13 deletion, is still a challenge, but t4;14 translocation, hypodiploidy, and deletion 13 ... are all no longer considered as high risk in the presence of protease inhibitors," he said. "It is nothing unique to carfilzomib; it’s just the class of protease inhibitors."

Dr. Jagannath said that even in patients with the problematic 17p13 deletion, researchers have used gene expression profiling to further delineate those at high and low risk, and that data clearly show that outcomes are improved in low-risk 17p13 deletion patients with the inclusion of the protease inhibitor bortezomib therapy.

Safety Data

The third poster features integrated safety data from 526 heavily pretreated patients receiving carfilzomib 20 mg/m² or 20-27 mg/m², showing that grade 3/4 treatment adverse events occurred in 80% of patients, but were characterized as mostly reversible and primarily hematologic in nature.

The most common grade 3 adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). There were no fatal hematologic events and no grade 4 or 5 bleeding reactions associated with thrombocytopenia, reported Dr. Seema Singhal, professor of medicine and director of the multiple myeloma program at Northwestern Memorial Hospital in Chicago, and her associates.

Cardiac events, some of which resulted in discontinuation or death, occurred. Cardiac failure events were reported in 7% with discontinuation due to heart failure in 2%, cardiac arrest in 1%, and myocardial ischemia in less than 1%.

"The extent to which these [events] were due to patients’ baseline comorbidities, toxicity from prior treatment, effects of multiple myeloma, carfilzomib itself, or a combination of these factors cannot be determined," the authors wrote.

Dr. Jagannath said the cardiac events do not represent a new signal.

The studies in the analyses were supported by Onyx. Dr. Ro is an employee of Onyx. Dr. Jakubowiak, Dr. Singhal, and Dr Jagannath reported financial relationships with several firms including Onyx.

SAN DIEGO – Mounting data from a federally funded follow-up to the BABY HUG study continue to demonstrate that hydroxyurea is a safe and effective treatment for young children with sickle cell anemia.

The results confirm findings published earlier this year from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), a randomized, placebo-controlled study sponsored by the National Institutes of Health and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BABY HUG showed that hydroxyurea administered to 9- to 18-month-old children with sickle cell anemia provides significant clinical benefits, including a decrease in pain crises, acute chest syndrome events, and need for transfusion and hospital admission (Lancet 2011; 377:1663-72).

Hydroxyurea is approved to prevent sickle cell complications in adults with sickle cell anemia, but it is not currently indicated for use in children. Dr. Zora R. Rogers discussed the new data during a press briefing prior to a presentation at the annual meeting of the American Society of Hematology.

"We need to complete the data analysis and to critically examine the growth and development of this population with respect to hydroxyurea use," lead author Dr. Rogers said of the follow-up study, which terminates on Dec. 31, 2011. "But on a macroscopic level there [do] not appear to be any differences observed."

In 2008 Dr. Rogers, professor of pediatrics at the University of Texas Southwestern Medical Center, Dallas, and her associates at 14 centers launched the BABY HUG Follow-Up Study I to assess the safety and efficacy of continued treatment with hydroxyurea in infants with sickle cell anemia. The population consisted of 163 children aged 28-44 months who had participated in the original BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. The researchers collected clinical and laboratory data every 6 months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

Of the 163 families that enrolled children in the follow-up study, 133 (82%) chose open-label hydroxyurea at the beginning of follow-up and every 6 months 65%-75% of the families reported that their children continued to take the drug. No patient developed intolerance or stopped permanently because of toxicity.

Dr. Rogers, clinical director of the bone marrow failure and general hematology program at Children’s Medical Center, Dallas, presented preliminary analyses as of Oct. 18, 2011, that amounted to 497 patient-years of follow-up. Compared with children who are not taking hydroxyurea, those who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency department visits (a rate of 29 vs. 54 per 100 patient-years, respectively), episodic transfusions (18 vs. 34 per 100 patient-years), and hospital admissions for any reason (73 vs. 132 per 100 patient-years), including acute chest syndrome or febrile illness.

In their abstract, the researchers pointed out that the decrease in acute chest syndrome episodes "is similar to the effect demonstrated with hydroxyurea use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of hydroxyurea therapy in older children and adults. The decrease in the rate of admission for febrile events in hydroxyurea-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain."

There were no differences between the two groups in hospitalization rates for painful events, including dactylitis. Two patients in the non-hydroxyurea group each had a stroke. There were also no differences between the two groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up, children taking hydroxyurea had persistently higher hemoglobin and mean corpuscular volume and lower white blood cell count and absolute neutrophil count, compared with those not taking the drug.

Dr. Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute (NHLBI), characterized the findings as important in efforts to get an early handle on the burden of disease associated with sickle cell anemia.

"The internists who inherit the patients who have gone through pediatric practitioners have a powerful sense that they reach adolescence doing pretty well, and then things kind of fall apart," Dr. Shurin said. "The clear evidence that prevention of organ damage and prevention of complications of sickle cell anemia would be much preferable to trying to manage once they develop has been the motivation" for this work.

The BABY HUG investigators "believe that ongoing follow-up of this cohort is essential to continue to define the potential benefits as the children grow and to observe for late toxicity," Dr. Rogers said. "We are in final discussions with the NHLBI for an additional contract in support of 5 more years of follow-up."

The researchers intend to use the current findings "in support of an FDA application potentially to allow an indication for the use of hydroxyurea in very young children," Dr. Rogers said. "We are also hoping that there will be an interest for the use of this medication in a liquid format, because it’s very hard to get a 1-year-old to take a capsule."

The follow-up study is funded by the National Heart, Lung, and Blood Institute and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SAN DIEGO – Mounting data from a federally funded follow-up to the BABY HUG study continue to demonstrate that hydroxyurea is a safe and effective treatment for young children with sickle cell anemia.

The results confirm findings published earlier this year from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), a randomized, placebo-controlled study sponsored by the National Institutes of Health and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BABY HUG showed that hydroxyurea administered to 9- to 18-month-old children with sickle cell anemia provides significant clinical benefits, including a decrease in pain crises, acute chest syndrome events, and need for transfusion and hospital admission (Lancet 2011; 377:1663-72).

Hydroxyurea is approved to prevent sickle cell complications in adults with sickle cell anemia, but it is not currently indicated for use in children. Dr. Zora R. Rogers discussed the new data during a press briefing prior to a presentation at the annual meeting of the American Society of Hematology.

"We need to complete the data analysis and to critically examine the growth and development of this population with respect to hydroxyurea use," lead author Dr. Rogers said of the follow-up study, which terminates on Dec. 31, 2011. "But on a macroscopic level there [do] not appear to be any differences observed."

In 2008 Dr. Rogers, professor of pediatrics at the University of Texas Southwestern Medical Center, Dallas, and her associates at 14 centers launched the BABY HUG Follow-Up Study I to assess the safety and efficacy of continued treatment with hydroxyurea in infants with sickle cell anemia. The population consisted of 163 children aged 28-44 months who had participated in the original BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. The researchers collected clinical and laboratory data every 6 months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

Of the 163 families that enrolled children in the follow-up study, 133 (82%) chose open-label hydroxyurea at the beginning of follow-up and every 6 months 65%-75% of the families reported that their children continued to take the drug. No patient developed intolerance or stopped permanently because of toxicity.

Dr. Rogers, clinical director of the bone marrow failure and general hematology program at Children’s Medical Center, Dallas, presented preliminary analyses as of Oct. 18, 2011, that amounted to 497 patient-years of follow-up. Compared with children who are not taking hydroxyurea, those who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency department visits (a rate of 29 vs. 54 per 100 patient-years, respectively), episodic transfusions (18 vs. 34 per 100 patient-years), and hospital admissions for any reason (73 vs. 132 per 100 patient-years), including acute chest syndrome or febrile illness.

In their abstract, the researchers pointed out that the decrease in acute chest syndrome episodes "is similar to the effect demonstrated with hydroxyurea use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of hydroxyurea therapy in older children and adults. The decrease in the rate of admission for febrile events in hydroxyurea-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain."

There were no differences between the two groups in hospitalization rates for painful events, including dactylitis. Two patients in the non-hydroxyurea group each had a stroke. There were also no differences between the two groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up, children taking hydroxyurea had persistently higher hemoglobin and mean corpuscular volume and lower white blood cell count and absolute neutrophil count, compared with those not taking the drug.

Dr. Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute (NHLBI), characterized the findings as important in efforts to get an early handle on the burden of disease associated with sickle cell anemia.

"The internists who inherit the patients who have gone through pediatric practitioners have a powerful sense that they reach adolescence doing pretty well, and then things kind of fall apart," Dr. Shurin said. "The clear evidence that prevention of organ damage and prevention of complications of sickle cell anemia would be much preferable to trying to manage once they develop has been the motivation" for this work.

The BABY HUG investigators "believe that ongoing follow-up of this cohort is essential to continue to define the potential benefits as the children grow and to observe for late toxicity," Dr. Rogers said. "We are in final discussions with the NHLBI for an additional contract in support of 5 more years of follow-up."

The researchers intend to use the current findings "in support of an FDA application potentially to allow an indication for the use of hydroxyurea in very young children," Dr. Rogers said. "We are also hoping that there will be an interest for the use of this medication in a liquid format, because it’s very hard to get a 1-year-old to take a capsule."

The follow-up study is funded by the National Heart, Lung, and Blood Institute and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SAN DIEGO – Mounting data from a federally funded follow-up to the BABY HUG study continue to demonstrate that hydroxyurea is a safe and effective treatment for young children with sickle cell anemia.

The results confirm findings published earlier this year from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), a randomized, placebo-controlled study sponsored by the National Institutes of Health and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BABY HUG showed that hydroxyurea administered to 9- to 18-month-old children with sickle cell anemia provides significant clinical benefits, including a decrease in pain crises, acute chest syndrome events, and need for transfusion and hospital admission (Lancet 2011; 377:1663-72).

Hydroxyurea is approved to prevent sickle cell complications in adults with sickle cell anemia, but it is not currently indicated for use in children. Dr. Zora R. Rogers discussed the new data during a press briefing prior to a presentation at the annual meeting of the American Society of Hematology.

"We need to complete the data analysis and to critically examine the growth and development of this population with respect to hydroxyurea use," lead author Dr. Rogers said of the follow-up study, which terminates on Dec. 31, 2011. "But on a macroscopic level there [do] not appear to be any differences observed."

In 2008 Dr. Rogers, professor of pediatrics at the University of Texas Southwestern Medical Center, Dallas, and her associates at 14 centers launched the BABY HUG Follow-Up Study I to assess the safety and efficacy of continued treatment with hydroxyurea in infants with sickle cell anemia. The population consisted of 163 children aged 28-44 months who had participated in the original BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. The researchers collected clinical and laboratory data every 6 months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

Of the 163 families that enrolled children in the follow-up study, 133 (82%) chose open-label hydroxyurea at the beginning of follow-up and every 6 months 65%-75% of the families reported that their children continued to take the drug. No patient developed intolerance or stopped permanently because of toxicity.

Dr. Rogers, clinical director of the bone marrow failure and general hematology program at Children’s Medical Center, Dallas, presented preliminary analyses as of Oct. 18, 2011, that amounted to 497 patient-years of follow-up. Compared with children who are not taking hydroxyurea, those who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency department visits (a rate of 29 vs. 54 per 100 patient-years, respectively), episodic transfusions (18 vs. 34 per 100 patient-years), and hospital admissions for any reason (73 vs. 132 per 100 patient-years), including acute chest syndrome or febrile illness.

In their abstract, the researchers pointed out that the decrease in acute chest syndrome episodes "is similar to the effect demonstrated with hydroxyurea use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of hydroxyurea therapy in older children and adults. The decrease in the rate of admission for febrile events in hydroxyurea-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain."

There were no differences between the two groups in hospitalization rates for painful events, including dactylitis. Two patients in the non-hydroxyurea group each had a stroke. There were also no differences between the two groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up, children taking hydroxyurea had persistently higher hemoglobin and mean corpuscular volume and lower white blood cell count and absolute neutrophil count, compared with those not taking the drug.

Dr. Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute (NHLBI), characterized the findings as important in efforts to get an early handle on the burden of disease associated with sickle cell anemia.

"The internists who inherit the patients who have gone through pediatric practitioners have a powerful sense that they reach adolescence doing pretty well, and then things kind of fall apart," Dr. Shurin said. "The clear evidence that prevention of organ damage and prevention of complications of sickle cell anemia would be much preferable to trying to manage once they develop has been the motivation" for this work.

The BABY HUG investigators "believe that ongoing follow-up of this cohort is essential to continue to define the potential benefits as the children grow and to observe for late toxicity," Dr. Rogers said. "We are in final discussions with the NHLBI for an additional contract in support of 5 more years of follow-up."

The researchers intend to use the current findings "in support of an FDA application potentially to allow an indication for the use of hydroxyurea in very young children," Dr. Rogers said. "We are also hoping that there will be an interest for the use of this medication in a liquid format, because it’s very hard to get a 1-year-old to take a capsule."

The follow-up study is funded by the National Heart, Lung, and Blood Institute and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SAN DIEGO – Long after the event, hematopoietic stem cell recipients still bear a heavier burden of physical and emotional problems than do their siblings, and greater use of specialized health care, according to investigators at the annual meeting of the American Society of Hematology.

In all, 74% of transplant survivors reported having a chronic health condition at least 10 years on, compared with 39% of age-matched siblings in the Bone Marrow Transplant Survivor Study.

"The difference was especially prominent for severe or life-threatening conditions: 25% of the survivors versus 8% of the siblings reported having a severe, life threatening condition," said Dr. Can-Lan Sun, director of survey research at City of Hope Medical Center in Duarte, Calif., on behalf of coauthors at a press briefing.

"Survivors were five times more likely to report a severe life-threatening condition than siblings," she added.

The cumulative incidence of chronic health conditions over 15 years of follow-up was 71%, and the cumulative incidence of severe, life-threatening events was 40%, the authors found.

"We have many more survivors than we used to, and we’re very thankful for that, but I think it’s important to realize that once a transplant is over, it’s not really over – and that there are some long-term effects either because of the transplant procedure, or because of the chemotherapy that the patient had to get to the transplant," commented Dr. Stephanie J. Lee, professor of medicine at the University of Washington, and a transplant specialist at the Fred Hutchinson Cancer Research Center, both in Seattle.

Dr. Lee moderated the briefing but was not involved in the study.

The authors conducted a retrospective study that surveyed 366 hematopoietic cell transplantation (HCT) survivors of at least 10 years’ duration and compared outcomes of chronic health conditions and psychological health with those of 309 aged-matched siblings. The severe and/or life-threatening conditions they considered included:

• Impaired hearing (loss not corrected by hearing aids).

• Legal blindness.

• Dialysis support.

• Gastrointestinal problems (surgery for intestinal obstruction, rectal or anal strictures, or cirrhosis.

• Cardiovascular disease (coronary artery disease, congestive heart failure, stroke).

• Joint replacement.

• Diabetes.

• Subsequent cancers.

The majority of survivors (65%) had received allogeneic transplants from a relative, 27% had autologous transplants, and 8% received HCT from unrelated donors. In all, 72% of patients had a conditioning regimen with total body irradiation and cyclophosphamide or etoposide, or both.

Indications for transplant were acute myeloid leukemia (28%), chronic myeloid leukemia (17%), acute lymphocytic leukemia (17%), non-Hodgkin’s lymphoma (11%), Hodgkin’s lymphoma (7%), aplastic anemia, or others (10%).

In an analysis adjusted for age at questionnaire, sex, race/ethnicity, education level attained, income and insurance status, they found that the relative risk (RR) for survivors to have any grade 1-4 condition was 2.16. The RR for having a grade 1 or 2 condition was 2.24, and for having a grade 3 or 4 condition was 5.64 (P less than .001 for all comparisons).

In addition, an analysis of adverse psychological outcomes, adjusted for the same factors, showed that survivors had an RR for somatic distress (unexplained physical symptoms such as pain, fatigue, etc.) of 2.73 (P = .03).

"Among survivors, females, those with low income, and those with poor health status were more likely to report somatic distress," Dr. Sun said.

In contrast, there were no significant differences between survivors and siblings in risk for anxiety, depression, or global distress.

Survivors also reported high use of health care services, with 78% reporting receiving a general physical examination within the past 2 years, and nearly two-thirds reporting that they had returned to the cancer center for ongoing care.

"As HCT continues to be a curative option for a variety of hematological malignancies, the burden of long-term physical and emotional morbidity formed by HCT recipients who have survived at least 10 years is substantial," Dr. Sun concluded.

The study was supported by a National Institutes of Health grant and a Leukemia & Lymphoma Society Scholar award to Dr. Sun. Neither she nor Dr. Lee had reported conflicts of interest.

SAN DIEGO – Long after the event, hematopoietic stem cell recipients still bear a heavier burden of physical and emotional problems than do their siblings, and greater use of specialized health care, according to investigators at the annual meeting of the American Society of Hematology.

In all, 74% of transplant survivors reported having a chronic health condition at least 10 years on, compared with 39% of age-matched siblings in the Bone Marrow Transplant Survivor Study.

"The difference was especially prominent for severe or life-threatening conditions: 25% of the survivors versus 8% of the siblings reported having a severe, life threatening condition," said Dr. Can-Lan Sun, director of survey research at City of Hope Medical Center in Duarte, Calif., on behalf of coauthors at a press briefing.

"Survivors were five times more likely to report a severe life-threatening condition than siblings," she added.

The cumulative incidence of chronic health conditions over 15 years of follow-up was 71%, and the cumulative incidence of severe, life-threatening events was 40%, the authors found.

"We have many more survivors than we used to, and we’re very thankful for that, but I think it’s important to realize that once a transplant is over, it’s not really over – and that there are some long-term effects either because of the transplant procedure, or because of the chemotherapy that the patient had to get to the transplant," commented Dr. Stephanie J. Lee, professor of medicine at the University of Washington, and a transplant specialist at the Fred Hutchinson Cancer Research Center, both in Seattle.

Dr. Lee moderated the briefing but was not involved in the study.

The authors conducted a retrospective study that surveyed 366 hematopoietic cell transplantation (HCT) survivors of at least 10 years’ duration and compared outcomes of chronic health conditions and psychological health with those of 309 aged-matched siblings. The severe and/or life-threatening conditions they considered included:

• Impaired hearing (loss not corrected by hearing aids).

• Legal blindness.

• Dialysis support.

• Gastrointestinal problems (surgery for intestinal obstruction, rectal or anal strictures, or cirrhosis.

• Cardiovascular disease (coronary artery disease, congestive heart failure, stroke).

• Joint replacement.

• Diabetes.

• Subsequent cancers.

The majority of survivors (65%) had received allogeneic transplants from a relative, 27% had autologous transplants, and 8% received HCT from unrelated donors. In all, 72% of patients had a conditioning regimen with total body irradiation and cyclophosphamide or etoposide, or both.

Indications for transplant were acute myeloid leukemia (28%), chronic myeloid leukemia (17%), acute lymphocytic leukemia (17%), non-Hodgkin’s lymphoma (11%), Hodgkin’s lymphoma (7%), aplastic anemia, or others (10%).

In an analysis adjusted for age at questionnaire, sex, race/ethnicity, education level attained, income and insurance status, they found that the relative risk (RR) for survivors to have any grade 1-4 condition was 2.16. The RR for having a grade 1 or 2 condition was 2.24, and for having a grade 3 or 4 condition was 5.64 (P less than .001 for all comparisons).

In addition, an analysis of adverse psychological outcomes, adjusted for the same factors, showed that survivors had an RR for somatic distress (unexplained physical symptoms such as pain, fatigue, etc.) of 2.73 (P = .03).

"Among survivors, females, those with low income, and those with poor health status were more likely to report somatic distress," Dr. Sun said.

In contrast, there were no significant differences between survivors and siblings in risk for anxiety, depression, or global distress.

Survivors also reported high use of health care services, with 78% reporting receiving a general physical examination within the past 2 years, and nearly two-thirds reporting that they had returned to the cancer center for ongoing care.

"As HCT continues to be a curative option for a variety of hematological malignancies, the burden of long-term physical and emotional morbidity formed by HCT recipients who have survived at least 10 years is substantial," Dr. Sun concluded.

The study was supported by a National Institutes of Health grant and a Leukemia & Lymphoma Society Scholar award to Dr. Sun. Neither she nor Dr. Lee had reported conflicts of interest.

SAN DIEGO – Long after the event, hematopoietic stem cell recipients still bear a heavier burden of physical and emotional problems than do their siblings, and greater use of specialized health care, according to investigators at the annual meeting of the American Society of Hematology.

In all, 74% of transplant survivors reported having a chronic health condition at least 10 years on, compared with 39% of age-matched siblings in the Bone Marrow Transplant Survivor Study.

"The difference was especially prominent for severe or life-threatening conditions: 25% of the survivors versus 8% of the siblings reported having a severe, life threatening condition," said Dr. Can-Lan Sun, director of survey research at City of Hope Medical Center in Duarte, Calif., on behalf of coauthors at a press briefing.

"Survivors were five times more likely to report a severe life-threatening condition than siblings," she added.

The cumulative incidence of chronic health conditions over 15 years of follow-up was 71%, and the cumulative incidence of severe, life-threatening events was 40%, the authors found.

"We have many more survivors than we used to, and we’re very thankful for that, but I think it’s important to realize that once a transplant is over, it’s not really over – and that there are some long-term effects either because of the transplant procedure, or because of the chemotherapy that the patient had to get to the transplant," commented Dr. Stephanie J. Lee, professor of medicine at the University of Washington, and a transplant specialist at the Fred Hutchinson Cancer Research Center, both in Seattle.

Dr. Lee moderated the briefing but was not involved in the study.

The authors conducted a retrospective study that surveyed 366 hematopoietic cell transplantation (HCT) survivors of at least 10 years’ duration and compared outcomes of chronic health conditions and psychological health with those of 309 aged-matched siblings. The severe and/or life-threatening conditions they considered included:

• Impaired hearing (loss not corrected by hearing aids).

• Legal blindness.

• Dialysis support.

• Gastrointestinal problems (surgery for intestinal obstruction, rectal or anal strictures, or cirrhosis.

• Cardiovascular disease (coronary artery disease, congestive heart failure, stroke).

• Joint replacement.

• Diabetes.

• Subsequent cancers.

The majority of survivors (65%) had received allogeneic transplants from a relative, 27% had autologous transplants, and 8% received HCT from unrelated donors. In all, 72% of patients had a conditioning regimen with total body irradiation and cyclophosphamide or etoposide, or both.

Indications for transplant were acute myeloid leukemia (28%), chronic myeloid leukemia (17%), acute lymphocytic leukemia (17%), non-Hodgkin’s lymphoma (11%), Hodgkin’s lymphoma (7%), aplastic anemia, or others (10%).

In an analysis adjusted for age at questionnaire, sex, race/ethnicity, education level attained, income and insurance status, they found that the relative risk (RR) for survivors to have any grade 1-4 condition was 2.16. The RR for having a grade 1 or 2 condition was 2.24, and for having a grade 3 or 4 condition was 5.64 (P less than .001 for all comparisons).

In addition, an analysis of adverse psychological outcomes, adjusted for the same factors, showed that survivors had an RR for somatic distress (unexplained physical symptoms such as pain, fatigue, etc.) of 2.73 (P = .03).

"Among survivors, females, those with low income, and those with poor health status were more likely to report somatic distress," Dr. Sun said.

In contrast, there were no significant differences between survivors and siblings in risk for anxiety, depression, or global distress.

Survivors also reported high use of health care services, with 78% reporting receiving a general physical examination within the past 2 years, and nearly two-thirds reporting that they had returned to the cancer center for ongoing care.

"As HCT continues to be a curative option for a variety of hematological malignancies, the burden of long-term physical and emotional morbidity formed by HCT recipients who have survived at least 10 years is substantial," Dr. Sun concluded.

The study was supported by a National Institutes of Health grant and a Leukemia & Lymphoma Society Scholar award to Dr. Sun. Neither she nor Dr. Lee had reported conflicts of interest.

SAN DIEGO – Filgrastim-mobilized peripheral blood stem cells convey no survival advantage over bone marrow transplants when the donor is not an HLA-identical sibling of the recipient, investigators have reported.

Two-year overall survival among 273 patients randomized to receive filgrastim (Neupogen)-mobilized peripheral blood stem cells (PBSC) from an unrelated donor was 51% in an intention-to-treat analysis, compared with 46% of 278 patients randomized to bone-marrow transplants (BMT), also from an unrelated donor (P=.288).

Moreover, filgrastim/PBSC was associated with an increased incidence of chronic extensive graft-versus host disease (GVHD) of 48%, compared with 32% for BMT (P less than .001). The incidence of acute GVHD did not differ between treatment types, Dr. Claudio Anasetti reported at the annual meeting of the American Society of Hematology.

PBSC was significantly better at engraftment, however, with only 7 patients (2.7%) experiencing either primary or secondary graft failure, compared with 24 (9.1%) of those who received BMT (P=.002).

Currently, around 75% of unrelated adult donor transplants use PBSC.

There are still some patients who might benefit from PBSC, he said, including those who are at increased risk for graft rejection. The incidence of rejection-related deaths was 8% among patients on BMT vs. 0% of patients on PBSC (P=.002). Patients at risk for rejection who do not receive pre-transplant immunosuppression, such as those with the myelodysplastic syndrome, may benefit more from PBSC, said Dr. Anasetti of the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla.

Similarly, heavily pre-treated patients with systemic infections who require rapid reconstitution with blood cells also may benefit from PBSC over bone marrow, he said.

Previous randomized trials in HLA-identical siblings demonstrated that filgrastim-mobilized PBSC compared to BMT improved engraftment kinetics, increased risks of acute and chronic GVHD, but also decreased relapse and improved survival in patients with high risk leukemia. Dr. Anasetti and his associates performed the current study to compare outcomes of PBSC and marrow transplants from unrelated donors.

A physician who performs stem-cell transplants but was not involved in the study said that the findings run contrary to what she and many of her colleagues had expected.

The investigators enrolled patients with acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, and mycosis fungoides from 50 centers in the United States and Canada. The patients were randomized on a 1:1 ratio to either PBSC or BMT and stratified by transplant center and disease risk.

A total of 5% of the 278 patients randomized to BMT did not receive a transplant, and 4.3% crossed over to PBSC. Of 273 assigned to PBSC, 4.3% were not transplanted, and 0.4% crossed over to BMT.

The majority of patients (90%) were adults age 21 or older, 47% had AML, 28% had high-risk disease, 48% underwent pre-transplant conditioning with cyclophosphamide plus total body irradiation, and 71% received tacrolimus (Prograf) plus methotrexate for GVHD prophylaxis.

Over 36-months median follow-up, there were no significant differences in either overall non-relapse deaths or in relapse rates, each of which occurred in about 30% of patients. Significantly more patients who received PBSC died from chronic GVHD: 21% compared with 10% of those who had received BMT (P=.002).

Patients on PBSC had better neutrophil engraftment at 5 days (P less than .001) and platelet engraftment at 7 days (P less than .001) than those who received BMT, however.

At 2-year follow-up, 57 of those who had received bone marrow were off of immunosuppressive therapy, compared with 37% of those who had received PBSC (P=.026).

Preplanned subset analyses showed no interactions between treatment arms in either disease risk, donor HLA matching, or patient age.

Future clinical research needs to focus on transplant approaches that can offset specific risks, such as prevention of graft failure with BMT, and prevention of acute and chronic GVHD with either source, Dr. Anasetti said.

The trial was funded by the National Heart, Lung and Blood Institute and National Cancer Institute. Dr. Anasetti disclosed off-label use of cyclophosphamide, busulfan, melphalan, fludarabine, anti-thymocyte globulin, and irradiation to eradicate malignancy, and tacrolimus, cyclosporine, methotrexate for GVHD prophylaxis. Co-author Daniel J. Weisdorf disclosed consulting for and receiving research funding from Genzyme. Co-author Peter Westervelt disclosed serving on a speakers bureau for Novartis.

SAN DIEGO – Filgrastim-mobilized peripheral blood stem cells convey no survival advantage over bone marrow transplants when the donor is not an HLA-identical sibling of the recipient, investigators have reported.

Two-year overall survival among 273 patients randomized to receive filgrastim (Neupogen)-mobilized peripheral blood stem cells (PBSC) from an unrelated donor was 51% in an intention-to-treat analysis, compared with 46% of 278 patients randomized to bone-marrow transplants (BMT), also from an unrelated donor (P=.288).

Moreover, filgrastim/PBSC was associated with an increased incidence of chronic extensive graft-versus host disease (GVHD) of 48%, compared with 32% for BMT (P less than .001). The incidence of acute GVHD did not differ between treatment types, Dr. Claudio Anasetti reported at the annual meeting of the American Society of Hematology.

PBSC was significantly better at engraftment, however, with only 7 patients (2.7%) experiencing either primary or secondary graft failure, compared with 24 (9.1%) of those who received BMT (P=.002).

Currently, around 75% of unrelated adult donor transplants use PBSC.

There are still some patients who might benefit from PBSC, he said, including those who are at increased risk for graft rejection. The incidence of rejection-related deaths was 8% among patients on BMT vs. 0% of patients on PBSC (P=.002). Patients at risk for rejection who do not receive pre-transplant immunosuppression, such as those with the myelodysplastic syndrome, may benefit more from PBSC, said Dr. Anasetti of the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla.

Similarly, heavily pre-treated patients with systemic infections who require rapid reconstitution with blood cells also may benefit from PBSC over bone marrow, he said.

Previous randomized trials in HLA-identical siblings demonstrated that filgrastim-mobilized PBSC compared to BMT improved engraftment kinetics, increased risks of acute and chronic GVHD, but also decreased relapse and improved survival in patients with high risk leukemia. Dr. Anasetti and his associates performed the current study to compare outcomes of PBSC and marrow transplants from unrelated donors.

A physician who performs stem-cell transplants but was not involved in the study said that the findings run contrary to what she and many of her colleagues had expected.

The investigators enrolled patients with acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, and mycosis fungoides from 50 centers in the United States and Canada. The patients were randomized on a 1:1 ratio to either PBSC or BMT and stratified by transplant center and disease risk.

A total of 5% of the 278 patients randomized to BMT did not receive a transplant, and 4.3% crossed over to PBSC. Of 273 assigned to PBSC, 4.3% were not transplanted, and 0.4% crossed over to BMT.

The majority of patients (90%) were adults age 21 or older, 47% had AML, 28% had high-risk disease, 48% underwent pre-transplant conditioning with cyclophosphamide plus total body irradiation, and 71% received tacrolimus (Prograf) plus methotrexate for GVHD prophylaxis.

Over 36-months median follow-up, there were no significant differences in either overall non-relapse deaths or in relapse rates, each of which occurred in about 30% of patients. Significantly more patients who received PBSC died from chronic GVHD: 21% compared with 10% of those who had received BMT (P=.002).

Patients on PBSC had better neutrophil engraftment at 5 days (P less than .001) and platelet engraftment at 7 days (P less than .001) than those who received BMT, however.

At 2-year follow-up, 57 of those who had received bone marrow were off of immunosuppressive therapy, compared with 37% of those who had received PBSC (P=.026).

Preplanned subset analyses showed no interactions between treatment arms in either disease risk, donor HLA matching, or patient age.

Future clinical research needs to focus on transplant approaches that can offset specific risks, such as prevention of graft failure with BMT, and prevention of acute and chronic GVHD with either source, Dr. Anasetti said.

The trial was funded by the National Heart, Lung and Blood Institute and National Cancer Institute. Dr. Anasetti disclosed off-label use of cyclophosphamide, busulfan, melphalan, fludarabine, anti-thymocyte globulin, and irradiation to eradicate malignancy, and tacrolimus, cyclosporine, methotrexate for GVHD prophylaxis. Co-author Daniel J. Weisdorf disclosed consulting for and receiving research funding from Genzyme. Co-author Peter Westervelt disclosed serving on a speakers bureau for Novartis.

SAN DIEGO – Filgrastim-mobilized peripheral blood stem cells convey no survival advantage over bone marrow transplants when the donor is not an HLA-identical sibling of the recipient, investigators have reported.

Two-year overall survival among 273 patients randomized to receive filgrastim (Neupogen)-mobilized peripheral blood stem cells (PBSC) from an unrelated donor was 51% in an intention-to-treat analysis, compared with 46% of 278 patients randomized to bone-marrow transplants (BMT), also from an unrelated donor (P=.288).

Moreover, filgrastim/PBSC was associated with an increased incidence of chronic extensive graft-versus host disease (GVHD) of 48%, compared with 32% for BMT (P less than .001). The incidence of acute GVHD did not differ between treatment types, Dr. Claudio Anasetti reported at the annual meeting of the American Society of Hematology.

PBSC was significantly better at engraftment, however, with only 7 patients (2.7%) experiencing either primary or secondary graft failure, compared with 24 (9.1%) of those who received BMT (P=.002).

Currently, around 75% of unrelated adult donor transplants use PBSC.

There are still some patients who might benefit from PBSC, he said, including those who are at increased risk for graft rejection. The incidence of rejection-related deaths was 8% among patients on BMT vs. 0% of patients on PBSC (P=.002). Patients at risk for rejection who do not receive pre-transplant immunosuppression, such as those with the myelodysplastic syndrome, may benefit more from PBSC, said Dr. Anasetti of the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla.

Similarly, heavily pre-treated patients with systemic infections who require rapid reconstitution with blood cells also may benefit from PBSC over bone marrow, he said.

Previous randomized trials in HLA-identical siblings demonstrated that filgrastim-mobilized PBSC compared to BMT improved engraftment kinetics, increased risks of acute and chronic GVHD, but also decreased relapse and improved survival in patients with high risk leukemia. Dr. Anasetti and his associates performed the current study to compare outcomes of PBSC and marrow transplants from unrelated donors.

A physician who performs stem-cell transplants but was not involved in the study said that the findings run contrary to what she and many of her colleagues had expected.

The investigators enrolled patients with acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, and mycosis fungoides from 50 centers in the United States and Canada. The patients were randomized on a 1:1 ratio to either PBSC or BMT and stratified by transplant center and disease risk.

A total of 5% of the 278 patients randomized to BMT did not receive a transplant, and 4.3% crossed over to PBSC. Of 273 assigned to PBSC, 4.3% were not transplanted, and 0.4% crossed over to BMT.

The majority of patients (90%) were adults age 21 or older, 47% had AML, 28% had high-risk disease, 48% underwent pre-transplant conditioning with cyclophosphamide plus total body irradiation, and 71% received tacrolimus (Prograf) plus methotrexate for GVHD prophylaxis.

Over 36-months median follow-up, there were no significant differences in either overall non-relapse deaths or in relapse rates, each of which occurred in about 30% of patients. Significantly more patients who received PBSC died from chronic GVHD: 21% compared with 10% of those who had received BMT (P=.002).

Patients on PBSC had better neutrophil engraftment at 5 days (P less than .001) and platelet engraftment at 7 days (P less than .001) than those who received BMT, however.

At 2-year follow-up, 57 of those who had received bone marrow were off of immunosuppressive therapy, compared with 37% of those who had received PBSC (P=.026).

Preplanned subset analyses showed no interactions between treatment arms in either disease risk, donor HLA matching, or patient age.

Future clinical research needs to focus on transplant approaches that can offset specific risks, such as prevention of graft failure with BMT, and prevention of acute and chronic GVHD with either source, Dr. Anasetti said.

The trial was funded by the National Heart, Lung and Blood Institute and National Cancer Institute. Dr. Anasetti disclosed off-label use of cyclophosphamide, busulfan, melphalan, fludarabine, anti-thymocyte globulin, and irradiation to eradicate malignancy, and tacrolimus, cyclosporine, methotrexate for GVHD prophylaxis. Co-author Daniel J. Weisdorf disclosed consulting for and receiving research funding from Genzyme. Co-author Peter Westervelt disclosed serving on a speakers bureau for Novartis.

ORLANDO – Although higher systolic blood pressure and LDL cholesterol are traditional risk factors for cardiovascular disease, each may have a different effect on the cerebrovascular and coronary systems.

Pooled analysis of three landmark studies done on the cholesterol-lowering agent atorvastatin in high-risk patients showed that higher baseline systolic blood pressure is predictive of a significantly higher risk of stroke. Meanwhile, higher baseline LDL cholesterol is predictive of a significantly higher risk of coronary events, the analysis showed.

The findings have implications on both research design and clinical practice, Dr. Prakash C. Deedwania, the study’s lead author, said at the annual scientific sessions of the American Heart Association.

Patients who might be at risk of both stroke and coronary events should be treated aggressively to reduce systolic blood pressure and LDL cholesterol, he said.

Dr. Deedwania and his colleagues pooled data on 21,727 patients from three trials: Treating to New Targets (TNT), which compared 10 mg with 80 mg atorvastatin in patients with stable coronary heart disease and LDL levels below 130 mg/dL (N. Engl. J. Med. 2005;352:1425-35), Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL), which compared high-dose (80 mg) atorvastatin with normal-dose (20-40 mg) simvastatin in post-MI patients (JAMA 2005;294:2437-45), and the Collaborative Atorvastatin Diabetes Study (CARDS), which compared 20 mg atorvastatin with placebo in patients with type 2 diabetes and without established coronary heart disease (Lancet 2004;364:685-96).

Results showed that with each 10-mm Hg increase in baseline systolic blood pressure, the risk of a fatal or nonfatal stroke increased by 16%. Meanwhile, each 10-mg/dL increase in baseline LDL cholesterol increased the risk of coronary events by 5%. Both differences were significantly different.

Dr. Deedwania said that the reduction in LDL cholesterol has been associated with a decrease in the risk of stroke, "but perhaps by a different mechanism."

The authors also looked at a subgroup of patients with type 2 diabetes (5,408 patients from the three trials), and found results consistent with the larger cohort.

Although systolic blood pressure is known to be a powerful predictor of stroke, many clinicians may not be aware that LDL cholesterol is not associated with an increased risk of stroke, said Dr. Deedwania. "What predicts baseline risk is different than what happens in treatment, so there are yet many lessons to be learned from these trials."

Dr. Deedwania has received research grants from Pfizer. He has been a consultant to and on the advisory boards of Pfizer and Novartis.

ORLANDO – Although higher systolic blood pressure and LDL cholesterol are traditional risk factors for cardiovascular disease, each may have a different effect on the cerebrovascular and coronary systems.

Pooled analysis of three landmark studies done on the cholesterol-lowering agent atorvastatin in high-risk patients showed that higher baseline systolic blood pressure is predictive of a significantly higher risk of stroke. Meanwhile, higher baseline LDL cholesterol is predictive of a significantly higher risk of coronary events, the analysis showed.

The findings have implications on both research design and clinical practice, Dr. Prakash C. Deedwania, the study’s lead author, said at the annual scientific sessions of the American Heart Association.

Patients who might be at risk of both stroke and coronary events should be treated aggressively to reduce systolic blood pressure and LDL cholesterol, he said.

Dr. Deedwania and his colleagues pooled data on 21,727 patients from three trials: Treating to New Targets (TNT), which compared 10 mg with 80 mg atorvastatin in patients with stable coronary heart disease and LDL levels below 130 mg/dL (N. Engl. J. Med. 2005;352:1425-35), Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL), which compared high-dose (80 mg) atorvastatin with normal-dose (20-40 mg) simvastatin in post-MI patients (JAMA 2005;294:2437-45), and the Collaborative Atorvastatin Diabetes Study (CARDS), which compared 20 mg atorvastatin with placebo in patients with type 2 diabetes and without established coronary heart disease (Lancet 2004;364:685-96).

Results showed that with each 10-mm Hg increase in baseline systolic blood pressure, the risk of a fatal or nonfatal stroke increased by 16%. Meanwhile, each 10-mg/dL increase in baseline LDL cholesterol increased the risk of coronary events by 5%. Both differences were significantly different.

Dr. Deedwania said that the reduction in LDL cholesterol has been associated with a decrease in the risk of stroke, "but perhaps by a different mechanism."

The authors also looked at a subgroup of patients with type 2 diabetes (5,408 patients from the three trials), and found results consistent with the larger cohort.

Although systolic blood pressure is known to be a powerful predictor of stroke, many clinicians may not be aware that LDL cholesterol is not associated with an increased risk of stroke, said Dr. Deedwania. "What predicts baseline risk is different than what happens in treatment, so there are yet many lessons to be learned from these trials."

Dr. Deedwania has received research grants from Pfizer. He has been a consultant to and on the advisory boards of Pfizer and Novartis.

ORLANDO – Although higher systolic blood pressure and LDL cholesterol are traditional risk factors for cardiovascular disease, each may have a different effect on the cerebrovascular and coronary systems.

Pooled analysis of three landmark studies done on the cholesterol-lowering agent atorvastatin in high-risk patients showed that higher baseline systolic blood pressure is predictive of a significantly higher risk of stroke. Meanwhile, higher baseline LDL cholesterol is predictive of a significantly higher risk of coronary events, the analysis showed.

The findings have implications on both research design and clinical practice, Dr. Prakash C. Deedwania, the study’s lead author, said at the annual scientific sessions of the American Heart Association.

Patients who might be at risk of both stroke and coronary events should be treated aggressively to reduce systolic blood pressure and LDL cholesterol, he said.

Dr. Deedwania and his colleagues pooled data on 21,727 patients from three trials: Treating to New Targets (TNT), which compared 10 mg with 80 mg atorvastatin in patients with stable coronary heart disease and LDL levels below 130 mg/dL (N. Engl. J. Med. 2005;352:1425-35), Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL), which compared high-dose (80 mg) atorvastatin with normal-dose (20-40 mg) simvastatin in post-MI patients (JAMA 2005;294:2437-45), and the Collaborative Atorvastatin Diabetes Study (CARDS), which compared 20 mg atorvastatin with placebo in patients with type 2 diabetes and without established coronary heart disease (Lancet 2004;364:685-96).

Results showed that with each 10-mm Hg increase in baseline systolic blood pressure, the risk of a fatal or nonfatal stroke increased by 16%. Meanwhile, each 10-mg/dL increase in baseline LDL cholesterol increased the risk of coronary events by 5%. Both differences were significantly different.

Dr. Deedwania said that the reduction in LDL cholesterol has been associated with a decrease in the risk of stroke, "but perhaps by a different mechanism."

The authors also looked at a subgroup of patients with type 2 diabetes (5,408 patients from the three trials), and found results consistent with the larger cohort.

Although systolic blood pressure is known to be a powerful predictor of stroke, many clinicians may not be aware that LDL cholesterol is not associated with an increased risk of stroke, said Dr. Deedwania. "What predicts baseline risk is different than what happens in treatment, so there are yet many lessons to be learned from these trials."

Dr. Deedwania has received research grants from Pfizer. He has been a consultant to and on the advisory boards of Pfizer and Novartis.

Begin by thinking about this diagnosis. If you don’t consider immunodeficiency during your routine evaluations, you are likely to miss one of these relatively rare conditions. Screening is of the utmost importance with more than 175 pediatric primary immunodeficiencies identified.

Considering immunodeficiencies appropriately is important – they represent sharp needles in the pediatrician’s haystack. You might be thinking: How am I going to recognize these important needles in my busy practice? My advice is to look for the hallmarks – infections that are recurrent, severe, or unusual.

Courtesy Children's Hospital of Philadelphia

I use a Statue of Liberty analogy. Give me your five sickest kids – the ones who hound your triage nurse, the ones who always page you after hours – and then think about immunodeficiency as a possible diagnosis. A child with recurrent infections who requires and responds to antibiotics frequently is a likely candidate.

Upper and lower respiratory tract infections are common in this patient population. About half of children with an immunodeficiency will have antibodies and will most typically present with involvement of the sinuses and/or the ears, including in some cases, bronchitis or pneumonia.

Severe combined immunodeficiency syndrome (SCIDS) is particularly alarming. If you practice in one of the states that require newborn screening for this condition – California, Louisiana, Massachusetts, New York, or Wisconsin – you are likely to receive a call at some point from your state laboratory. The number of calls you get alerting you to a positive result will vary by the size of your practice: SCIDS affects about 1 in 50,000 live births. There was a case in Wisconsin where a baby with SCIDS was identified quickly and cured (J. Allergy Clin. Immunol. 2011;127:535-38).

A newborn with SCIDS lacks the capacity to make functional T cells, and there is a movement to expand this screening to all 50 states.

As with any confirmed immunodeficiency, working in concert with an immunologist becomes essential. Expertise is important because there are therapeutic options for almost every patient with a primary immunodeficiency diagnosis. A subspecialist can help you devise an effective management plan. It is a matter of pediatricians feeling empowered, not feeling that children with primary immunodeficiencies are too complex to manage.

I am fine with a pediatrician calling for a direct referral. It is appropriate not to manage the diagnostic evaluation of these children if you feel uncomfortable. With that said, there are opportunities for pediatricians to manage these patients as well. I know some pediatricians are as adept at this as I am.

For example, you can screen a child with a suspected immunodeficiency for the presence of antibodies. Keep quantity and quality in mind. Quantity is a check of how full the tank is; for example, assess their levels of IgG, IgM, and IgA.

Quality assessment can be more challenging, but there are appropriate, point-of-contact screenings you can perform without too much effort. Most importantly these would include checking the antibody titers against vaccines you have provided, such as a tetanus titer or pneumococcal titers.

A complete blood count with differential, for example, provides important information, including the percentage and number of lymphocytes and neutrophils. If the absolute levels are low, then it becomes relevant to think: Why? Viral suppression is a true cause, but it’s overrated, so be sure to reevaluate a low count and remember to consider immunodeficiency if a low value persists.

If you suspect immunodeficiency in a baby, for example, check the infant’s lymphocyte count against the age-specific normal value. This varies, but the lower limit for normal for a healthy child under 1 year of age is about 3,500/mcL.

This might surprise you, but a child with low or no lymphocytes can quickly require emergency medical attention.

Other tests are more in the domain of the specialist or more appropriate in specific situations. In addition, the assay order forms and specialty laboratories can be tricky. Right next to IgG, for example, the IgG subclasses are often listed. These subclass evaluations are expensive and of little value in routine clinical assessment.

The bottom line is: Think about primary immunodeficiency. If you are uncomfortable in carrying forward a diagnostic evaluation – call an immunologist. We are happy to help. Statistically speaking, the needle is in your haystack. A pediatric practice looking after 10,000 children should be following 5 with primary immunodeficiency. Do you know who yours are?

This column, "Subspecialist Consult," appears regularly in Pediatric News, an Elsevier publication. Dr. Orange is a pediatric immunologist in the division of allergy and immunology at Children’s Hospital of Philadelphia. He disclosed that he is a medical adviser to the Immunodeficiency Foundation and a consultant to three manufacturers of immunoglobulin therapies: Baxter Healthcare, Talecris Biotherapeutics, and CSL Behring. He also receives research grants from Octapharma USA.

Begin by thinking about this diagnosis. If you don’t consider immunodeficiency during your routine evaluations, you are likely to miss one of these relatively rare conditions. Screening is of the utmost importance with more than 175 pediatric primary immunodeficiencies identified.

Considering immunodeficiencies appropriately is important – they represent sharp needles in the pediatrician’s haystack. You might be thinking: How am I going to recognize these important needles in my busy practice? My advice is to look for the hallmarks – infections that are recurrent, severe, or unusual.

Courtesy Children's Hospital of Philadelphia

I use a Statue of Liberty analogy. Give me your five sickest kids – the ones who hound your triage nurse, the ones who always page you after hours – and then think about immunodeficiency as a possible diagnosis. A child with recurrent infections who requires and responds to antibiotics frequently is a likely candidate.

Upper and lower respiratory tract infections are common in this patient population. About half of children with an immunodeficiency will have antibodies and will most typically present with involvement of the sinuses and/or the ears, including in some cases, bronchitis or pneumonia.

Severe combined immunodeficiency syndrome (SCIDS) is particularly alarming. If you practice in one of the states that require newborn screening for this condition – California, Louisiana, Massachusetts, New York, or Wisconsin – you are likely to receive a call at some point from your state laboratory. The number of calls you get alerting you to a positive result will vary by the size of your practice: SCIDS affects about 1 in 50,000 live births. There was a case in Wisconsin where a baby with SCIDS was identified quickly and cured (J. Allergy Clin. Immunol. 2011;127:535-38).

A newborn with SCIDS lacks the capacity to make functional T cells, and there is a movement to expand this screening to all 50 states.

As with any confirmed immunodeficiency, working in concert with an immunologist becomes essential. Expertise is important because there are therapeutic options for almost every patient with a primary immunodeficiency diagnosis. A subspecialist can help you devise an effective management plan. It is a matter of pediatricians feeling empowered, not feeling that children with primary immunodeficiencies are too complex to manage.

I am fine with a pediatrician calling for a direct referral. It is appropriate not to manage the diagnostic evaluation of these children if you feel uncomfortable. With that said, there are opportunities for pediatricians to manage these patients as well. I know some pediatricians are as adept at this as I am.

For example, you can screen a child with a suspected immunodeficiency for the presence of antibodies. Keep quantity and quality in mind. Quantity is a check of how full the tank is; for example, assess their levels of IgG, IgM, and IgA.

Quality assessment can be more challenging, but there are appropriate, point-of-contact screenings you can perform without too much effort. Most importantly these would include checking the antibody titers against vaccines you have provided, such as a tetanus titer or pneumococcal titers.

A complete blood count with differential, for example, provides important information, including the percentage and number of lymphocytes and neutrophils. If the absolute levels are low, then it becomes relevant to think: Why? Viral suppression is a true cause, but it’s overrated, so be sure to reevaluate a low count and remember to consider immunodeficiency if a low value persists.

If you suspect immunodeficiency in a baby, for example, check the infant’s lymphocyte count against the age-specific normal value. This varies, but the lower limit for normal for a healthy child under 1 year of age is about 3,500/mcL.

This might surprise you, but a child with low or no lymphocytes can quickly require emergency medical attention.

Other tests are more in the domain of the specialist or more appropriate in specific situations. In addition, the assay order forms and specialty laboratories can be tricky. Right next to IgG, for example, the IgG subclasses are often listed. These subclass evaluations are expensive and of little value in routine clinical assessment.

The bottom line is: Think about primary immunodeficiency. If you are uncomfortable in carrying forward a diagnostic evaluation – call an immunologist. We are happy to help. Statistically speaking, the needle is in your haystack. A pediatric practice looking after 10,000 children should be following 5 with primary immunodeficiency. Do you know who yours are?

This column, "Subspecialist Consult," appears regularly in Pediatric News, an Elsevier publication. Dr. Orange is a pediatric immunologist in the division of allergy and immunology at Children’s Hospital of Philadelphia. He disclosed that he is a medical adviser to the Immunodeficiency Foundation and a consultant to three manufacturers of immunoglobulin therapies: Baxter Healthcare, Talecris Biotherapeutics, and CSL Behring. He also receives research grants from Octapharma USA.

Begin by thinking about this diagnosis. If you don’t consider immunodeficiency during your routine evaluations, you are likely to miss one of these relatively rare conditions. Screening is of the utmost importance with more than 175 pediatric primary immunodeficiencies identified.

Considering immunodeficiencies appropriately is important – they represent sharp needles in the pediatrician’s haystack. You might be thinking: How am I going to recognize these important needles in my busy practice? My advice is to look for the hallmarks – infections that are recurrent, severe, or unusual.

Courtesy Children's Hospital of Philadelphia

I use a Statue of Liberty analogy. Give me your five sickest kids – the ones who hound your triage nurse, the ones who always page you after hours – and then think about immunodeficiency as a possible diagnosis. A child with recurrent infections who requires and responds to antibiotics frequently is a likely candidate.

Upper and lower respiratory tract infections are common in this patient population. About half of children with an immunodeficiency will have antibodies and will most typically present with involvement of the sinuses and/or the ears, including in some cases, bronchitis or pneumonia.

Severe combined immunodeficiency syndrome (SCIDS) is particularly alarming. If you practice in one of the states that require newborn screening for this condition – California, Louisiana, Massachusetts, New York, or Wisconsin – you are likely to receive a call at some point from your state laboratory. The number of calls you get alerting you to a positive result will vary by the size of your practice: SCIDS affects about 1 in 50,000 live births. There was a case in Wisconsin where a baby with SCIDS was identified quickly and cured (J. Allergy Clin. Immunol. 2011;127:535-38).

A newborn with SCIDS lacks the capacity to make functional T cells, and there is a movement to expand this screening to all 50 states.

As with any confirmed immunodeficiency, working in concert with an immunologist becomes essential. Expertise is important because there are therapeutic options for almost every patient with a primary immunodeficiency diagnosis. A subspecialist can help you devise an effective management plan. It is a matter of pediatricians feeling empowered, not feeling that children with primary immunodeficiencies are too complex to manage.

I am fine with a pediatrician calling for a direct referral. It is appropriate not to manage the diagnostic evaluation of these children if you feel uncomfortable. With that said, there are opportunities for pediatricians to manage these patients as well. I know some pediatricians are as adept at this as I am.

For example, you can screen a child with a suspected immunodeficiency for the presence of antibodies. Keep quantity and quality in mind. Quantity is a check of how full the tank is; for example, assess their levels of IgG, IgM, and IgA.

Quality assessment can be more challenging, but there are appropriate, point-of-contact screenings you can perform without too much effort. Most importantly these would include checking the antibody titers against vaccines you have provided, such as a tetanus titer or pneumococcal titers.

A complete blood count with differential, for example, provides important information, including the percentage and number of lymphocytes and neutrophils. If the absolute levels are low, then it becomes relevant to think: Why? Viral suppression is a true cause, but it’s overrated, so be sure to reevaluate a low count and remember to consider immunodeficiency if a low value persists.

If you suspect immunodeficiency in a baby, for example, check the infant’s lymphocyte count against the age-specific normal value. This varies, but the lower limit for normal for a healthy child under 1 year of age is about 3,500/mcL.

This might surprise you, but a child with low or no lymphocytes can quickly require emergency medical attention.

Other tests are more in the domain of the specialist or more appropriate in specific situations. In addition, the assay order forms and specialty laboratories can be tricky. Right next to IgG, for example, the IgG subclasses are often listed. These subclass evaluations are expensive and of little value in routine clinical assessment.

The bottom line is: Think about primary immunodeficiency. If you are uncomfortable in carrying forward a diagnostic evaluation – call an immunologist. We are happy to help. Statistically speaking, the needle is in your haystack. A pediatric practice looking after 10,000 children should be following 5 with primary immunodeficiency. Do you know who yours are?

This column, "Subspecialist Consult," appears regularly in Pediatric News, an Elsevier publication. Dr. Orange is a pediatric immunologist in the division of allergy and immunology at Children’s Hospital of Philadelphia. He disclosed that he is a medical adviser to the Immunodeficiency Foundation and a consultant to three manufacturers of immunoglobulin therapies: Baxter Healthcare, Talecris Biotherapeutics, and CSL Behring. He also receives research grants from Octapharma USA.

Clostridium difficile has been on the radar of infectious disease (ID) experts for the better part of a decade now. But how mindful are hospitalists of the problem, and how seriously are they taking it?

“I think we’re getting there,” says Danielle Scheurer, MD, MSCR, SFHM, a hospitalist and medical director of quality at the Medical University of South Carolina in Charleston. But she adds, “Because the bugs are invisible, you feel a little bit disconnected from your direct role in all this.”

Stuart Cohen, MD, an ID expert at the University of California Davis and a fellow with the Infectious Diseases Society of America, says not everyone is as concerned about C. diff as they should be.

“I think most people still see C. diff as just basically being a nuisance, and so they don’t really take it quite so seriously. Until somebody sees a patient have to get a colectomy or die from C. diff, I don’t think that there’s necessarily an appreciation to the severity of the illness,” he says. “You don’t really get this sense that it’s anything other than, ‘Well, we’ll just give them some vancomycin or we’ll just give them some metronidazole and we’ll take care of it.’”

Ketino Kobaidze, MD, a hospitalist at Emory University Hospital Midtown in Atlanta, says she thinks hospitalists should be more involved in antibiotic stewardship efforts and in research efforts to combat C. diff.

“I’m sure everybody knows and everybody takes it into consideration,” she says. But she also says not all hospitalists view C. diff as an acute problem that warrants urgent treatment “or we might be in trouble,” she says. “I’m not sure about that.”

Dr. Scheurer says the solution to treating C. diff properly is keeping a mindset on the safety of your patients. “Then it can motivate you and your group,” she says. “Every single number affects a person. It’s not just a rate. Zero is the goal.”

Tom Collins is a freelance medical writer based in Florida.

Clostridium difficile has been on the radar of infectious disease (ID) experts for the better part of a decade now. But how mindful are hospitalists of the problem, and how seriously are they taking it?

“I think we’re getting there,” says Danielle Scheurer, MD, MSCR, SFHM, a hospitalist and medical director of quality at the Medical University of South Carolina in Charleston. But she adds, “Because the bugs are invisible, you feel a little bit disconnected from your direct role in all this.”

Stuart Cohen, MD, an ID expert at the University of California Davis and a fellow with the Infectious Diseases Society of America, says not everyone is as concerned about C. diff as they should be.

“I think most people still see C. diff as just basically being a nuisance, and so they don’t really take it quite so seriously. Until somebody sees a patient have to get a colectomy or die from C. diff, I don’t think that there’s necessarily an appreciation to the severity of the illness,” he says. “You don’t really get this sense that it’s anything other than, ‘Well, we’ll just give them some vancomycin or we’ll just give them some metronidazole and we’ll take care of it.’”

Ketino Kobaidze, MD, a hospitalist at Emory University Hospital Midtown in Atlanta, says she thinks hospitalists should be more involved in antibiotic stewardship efforts and in research efforts to combat C. diff.

“I’m sure everybody knows and everybody takes it into consideration,” she says. But she also says not all hospitalists view C. diff as an acute problem that warrants urgent treatment “or we might be in trouble,” she says. “I’m not sure about that.”

Dr. Scheurer says the solution to treating C. diff properly is keeping a mindset on the safety of your patients. “Then it can motivate you and your group,” she says. “Every single number affects a person. It’s not just a rate. Zero is the goal.”

Tom Collins is a freelance medical writer based in Florida.

Clostridium difficile has been on the radar of infectious disease (ID) experts for the better part of a decade now. But how mindful are hospitalists of the problem, and how seriously are they taking it?

“I think we’re getting there,” says Danielle Scheurer, MD, MSCR, SFHM, a hospitalist and medical director of quality at the Medical University of South Carolina in Charleston. But she adds, “Because the bugs are invisible, you feel a little bit disconnected from your direct role in all this.”

Stuart Cohen, MD, an ID expert at the University of California Davis and a fellow with the Infectious Diseases Society of America, says not everyone is as concerned about C. diff as they should be.

“I think most people still see C. diff as just basically being a nuisance, and so they don’t really take it quite so seriously. Until somebody sees a patient have to get a colectomy or die from C. diff, I don’t think that there’s necessarily an appreciation to the severity of the illness,” he says. “You don’t really get this sense that it’s anything other than, ‘Well, we’ll just give them some vancomycin or we’ll just give them some metronidazole and we’ll take care of it.’”

Ketino Kobaidze, MD, a hospitalist at Emory University Hospital Midtown in Atlanta, says she thinks hospitalists should be more involved in antibiotic stewardship efforts and in research efforts to combat C. diff.

“I’m sure everybody knows and everybody takes it into consideration,” she says. But she also says not all hospitalists view C. diff as an acute problem that warrants urgent treatment “or we might be in trouble,” she says. “I’m not sure about that.”

Dr. Scheurer says the solution to treating C. diff properly is keeping a mindset on the safety of your patients. “Then it can motivate you and your group,” she says. “Every single number affects a person. It’s not just a rate. Zero is the goal.”

Tom Collins is a freelance medical writer based in Florida.