Anemia

Research Hospital

Dosing of hydroxyurea (HU) in young patients with sickle cell anemia (SCA) should target a fetal hemoglobin (HbF) level above 20%, according to researchers.

Their study, HUSTLE, showed that children and adolescents who received a maximum tolerated dose (MTD) of HU were able to achieve HbF levels above 20%.

And patients who achieved such HbF levels had a significantly lower risk of hospitalization for any reason, including vaso-occlusive crisis, acute chest syndrome, and fever.

Jeremie Estepp, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these results in the American Journal of Hematology.

“Our analysis showed that, using this approach, hospitalizations for the average patient fell to less than 1 every couple of years rather than 4 to 6 annually,” Dr Estepp said. “This frees children from the fevers, pain, and other symptoms of this disease and gives them and their families more chances to enjoy childhood and adolescence.”

The study enrolled 230 SCA patients. Most had the HbSS genotype (n=214; 93%), although 7% (n=16) had HbSb⁰ thalassemia. The patients’ median age at HU initiation was 7.4 years (range, 6 months to 17.9 years). The mean HbF level at enrollment was 9.7%, and the median was 7.9% (range, 1.0-32.9%).

The researchers used a dose-escalation approach to determine the MTD of HU for each of the patients in this study. The MTD was defined by an absolute neutrophil count of 2000-4000 x 10⁶/L or the presence of hematologic toxicity. The maximum absolute dose was 35 mg/kg/day or 2000 mg/day (whichever came first).

The mean daily dose of HU at the MTD was 26.7 mg/kg/day, and the median was 28.0 mg/kg/day (range, 13.0 to 35.0 mg/kg/day).

Three-quarters of patients (75.2%, 173/230) attained the MTD at the time of data censoring. Patients were followed for up to 4 years after study entry.

As far as treatment compliance, there were complete medication dispensation records available for 96% (220/230) of patients. And the patients were in possession of HU a mean of 93.6% of the time.

The researchers found that administering HU at the MTD resulted in a mean HbF of 26.7% and a median of 21.7% (interquartile range, 16.2% to 27.8%).

And the odds of being hospitalized were higher when a patient’s HbF level was less than 21%. The odds ratios for hospitalization were as follows:

• 4.1 for fever
• 2.6 for acute chest syndrome
• 2.2 for vaso-occlusive crisis
• 2.1 for any reason.

“These results support a hydroxyurea dosing strategy designed to produce fetal hemoglobin levels that exceed 20% in an effort to decrease hospitalization of children with sickle cell disease,” Dr Estepp said.

He and his colleagues are now conducting a multicenter trial to determine if toddlers with SCA would benefit from a similar dosing strategy or would respond better to a standard dose.

Research Hospital

Dosing of hydroxyurea (HU) in young patients with sickle cell anemia (SCA) should target a fetal hemoglobin (HbF) level above 20%, according to researchers.

Their study, HUSTLE, showed that children and adolescents who received a maximum tolerated dose (MTD) of HU were able to achieve HbF levels above 20%.

And patients who achieved such HbF levels had a significantly lower risk of hospitalization for any reason, including vaso-occlusive crisis, acute chest syndrome, and fever.

Jeremie Estepp, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these results in the American Journal of Hematology.

“Our analysis showed that, using this approach, hospitalizations for the average patient fell to less than 1 every couple of years rather than 4 to 6 annually,” Dr Estepp said. “This frees children from the fevers, pain, and other symptoms of this disease and gives them and their families more chances to enjoy childhood and adolescence.”

The study enrolled 230 SCA patients. Most had the HbSS genotype (n=214; 93%), although 7% (n=16) had HbSb⁰ thalassemia. The patients’ median age at HU initiation was 7.4 years (range, 6 months to 17.9 years). The mean HbF level at enrollment was 9.7%, and the median was 7.9% (range, 1.0-32.9%).

The researchers used a dose-escalation approach to determine the MTD of HU for each of the patients in this study. The MTD was defined by an absolute neutrophil count of 2000-4000 x 10⁶/L or the presence of hematologic toxicity. The maximum absolute dose was 35 mg/kg/day or 2000 mg/day (whichever came first).

The mean daily dose of HU at the MTD was 26.7 mg/kg/day, and the median was 28.0 mg/kg/day (range, 13.0 to 35.0 mg/kg/day).

Three-quarters of patients (75.2%, 173/230) attained the MTD at the time of data censoring. Patients were followed for up to 4 years after study entry.

As far as treatment compliance, there were complete medication dispensation records available for 96% (220/230) of patients. And the patients were in possession of HU a mean of 93.6% of the time.

The researchers found that administering HU at the MTD resulted in a mean HbF of 26.7% and a median of 21.7% (interquartile range, 16.2% to 27.8%).

And the odds of being hospitalized were higher when a patient’s HbF level was less than 21%. The odds ratios for hospitalization were as follows:

• 4.1 for fever
• 2.6 for acute chest syndrome
• 2.2 for vaso-occlusive crisis
• 2.1 for any reason.

“These results support a hydroxyurea dosing strategy designed to produce fetal hemoglobin levels that exceed 20% in an effort to decrease hospitalization of children with sickle cell disease,” Dr Estepp said.

He and his colleagues are now conducting a multicenter trial to determine if toddlers with SCA would benefit from a similar dosing strategy or would respond better to a standard dose.

Research Hospital

Dosing of hydroxyurea (HU) in young patients with sickle cell anemia (SCA) should target a fetal hemoglobin (HbF) level above 20%, according to researchers.

Their study, HUSTLE, showed that children and adolescents who received a maximum tolerated dose (MTD) of HU were able to achieve HbF levels above 20%.

And patients who achieved such HbF levels had a significantly lower risk of hospitalization for any reason, including vaso-occlusive crisis, acute chest syndrome, and fever.

Jeremie Estepp, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these results in the American Journal of Hematology.

“Our analysis showed that, using this approach, hospitalizations for the average patient fell to less than 1 every couple of years rather than 4 to 6 annually,” Dr Estepp said. “This frees children from the fevers, pain, and other symptoms of this disease and gives them and their families more chances to enjoy childhood and adolescence.”

The study enrolled 230 SCA patients. Most had the HbSS genotype (n=214; 93%), although 7% (n=16) had HbSb⁰ thalassemia. The patients’ median age at HU initiation was 7.4 years (range, 6 months to 17.9 years). The mean HbF level at enrollment was 9.7%, and the median was 7.9% (range, 1.0-32.9%).

The researchers used a dose-escalation approach to determine the MTD of HU for each of the patients in this study. The MTD was defined by an absolute neutrophil count of 2000-4000 x 10⁶/L or the presence of hematologic toxicity. The maximum absolute dose was 35 mg/kg/day or 2000 mg/day (whichever came first).

The mean daily dose of HU at the MTD was 26.7 mg/kg/day, and the median was 28.0 mg/kg/day (range, 13.0 to 35.0 mg/kg/day).

Three-quarters of patients (75.2%, 173/230) attained the MTD at the time of data censoring. Patients were followed for up to 4 years after study entry.

As far as treatment compliance, there were complete medication dispensation records available for 96% (220/230) of patients. And the patients were in possession of HU a mean of 93.6% of the time.

The researchers found that administering HU at the MTD resulted in a mean HbF of 26.7% and a median of 21.7% (interquartile range, 16.2% to 27.8%).

And the odds of being hospitalized were higher when a patient’s HbF level was less than 21%. The odds ratios for hospitalization were as follows:

• 4.1 for fever
• 2.6 for acute chest syndrome
• 2.2 for vaso-occlusive crisis
• 2.1 for any reason.

“These results support a hydroxyurea dosing strategy designed to produce fetal hemoglobin levels that exceed 20% in an effort to decrease hospitalization of children with sickle cell disease,” Dr Estepp said.

He and his colleagues are now conducting a multicenter trial to determine if toddlers with SCA would benefit from a similar dosing strategy or would respond better to a standard dose.

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for romiplostim (Nplate^®) to include children.

The CHMP is recommending authorization of romiplostim to treat patients age 1 and older who have chronic immune thrombocytopenia (ITP) that is refractory to other treatments.

The committee’s opinion will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, a centralized marketing authorization will be granted that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The recommendation for romiplostim was based on 5 studies of the drug in children with ITP. This includes 4 completed studies—a phase 1/2, a phase 3, and 2 long-term safety and efficacy studies—and 1 ongoing long-term study.

Results from the phase 1/2 trial were published in Blood in 2011. Phase 3 results were published in The Lancet in April of last year.

And results from 2 of the long-term trials were presented at 22nd Congress of the European Hematology Association in June (abstract P367 and abstract P727).

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for romiplostim (Nplate^®) to include children.

The CHMP is recommending authorization of romiplostim to treat patients age 1 and older who have chronic immune thrombocytopenia (ITP) that is refractory to other treatments.

The committee’s opinion will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, a centralized marketing authorization will be granted that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The recommendation for romiplostim was based on 5 studies of the drug in children with ITP. This includes 4 completed studies—a phase 1/2, a phase 3, and 2 long-term safety and efficacy studies—and 1 ongoing long-term study.

Results from the phase 1/2 trial were published in Blood in 2011. Phase 3 results were published in The Lancet in April of last year.

And results from 2 of the long-term trials were presented at 22nd Congress of the European Hematology Association in June (abstract P367 and abstract P727).

Photo by Bill Branson

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for romiplostim (Nplate^®) to include children.

The CHMP is recommending authorization of romiplostim to treat patients age 1 and older who have chronic immune thrombocytopenia (ITP) that is refractory to other treatments.

The committee’s opinion will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, a centralized marketing authorization will be granted that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The recommendation for romiplostim was based on 5 studies of the drug in children with ITP. This includes 4 completed studies—a phase 1/2, a phase 3, and 2 long-term safety and efficacy studies—and 1 ongoing long-term study.

Results from the phase 1/2 trial were published in Blood in 2011. Phase 3 results were published in The Lancet in April of last year.

And results from 2 of the long-term trials were presented at 22nd Congress of the European Hematology Association in June (abstract P367 and abstract P727).

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to ACH-4471 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

And the European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products has recommended the drug receive orphan status for the same indication in the European Economic Area.

ACH-4471 is a factor D inhibitor being developed by Achillion Pharmaceuticals, Inc.

In April, the company announced the initiation of a phase 2, three-month, dose-ranging trial with ACH-4471 for patients with untreated PNH (NCT03053102).

The primary objective of the trial is to assess the change from baseline in serum lactate dehydrogenase (LDH) levels. Secondary endpoints include changes in hemoglobin, PNH red blood cells, fatigue score (FACIT scale), changes in levels of complement pathway biomarkers such as Bb and factor D, pharmacokinetics, and safety.

The protocol allows for intra-patient dose-escalation. Patients initially receive 100 mg or 150 mg of ACH-4471 three times daily, and doses may be increased during the treatment period.

After patients complete 3 months of treatment and investigators have assessed safety and clinical benefit, patients may be enrolled in the long-term extension trial (NCT03181633).

To date, 200 mg three times daily has been the highest dose of ACH-4471 administered. And Achillion has collected data on 4 patients.

Two of the patients have completed the 3-month trial and entered the long-term extension trial. One patient continues to receive dosing in the 3-month trial, and the fourth patient voluntarily withdrew from the trial on day 41 for reasons unrelated to safety.

Thus far, ACH-4471 has produced clinically meaningful complement inhibition and demonstrated a favorable tolerability profile, with no reports of clinically meaningful increases in liver enzymes. ACH-4471 has improved LDH, hemoglobin, fatigue score, and other measures of response, including PNH clone size.

FDA’s orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

EMA’s orphan designation

The EMA’s orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. It also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to ACH-4471 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

And the European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products has recommended the drug receive orphan status for the same indication in the European Economic Area.

ACH-4471 is a factor D inhibitor being developed by Achillion Pharmaceuticals, Inc.

In April, the company announced the initiation of a phase 2, three-month, dose-ranging trial with ACH-4471 for patients with untreated PNH (NCT03053102).

The primary objective of the trial is to assess the change from baseline in serum lactate dehydrogenase (LDH) levels. Secondary endpoints include changes in hemoglobin, PNH red blood cells, fatigue score (FACIT scale), changes in levels of complement pathway biomarkers such as Bb and factor D, pharmacokinetics, and safety.

The protocol allows for intra-patient dose-escalation. Patients initially receive 100 mg or 150 mg of ACH-4471 three times daily, and doses may be increased during the treatment period.

After patients complete 3 months of treatment and investigators have assessed safety and clinical benefit, patients may be enrolled in the long-term extension trial (NCT03181633).

To date, 200 mg three times daily has been the highest dose of ACH-4471 administered. And Achillion has collected data on 4 patients.

Two of the patients have completed the 3-month trial and entered the long-term extension trial. One patient continues to receive dosing in the 3-month trial, and the fourth patient voluntarily withdrew from the trial on day 41 for reasons unrelated to safety.

Thus far, ACH-4471 has produced clinically meaningful complement inhibition and demonstrated a favorable tolerability profile, with no reports of clinically meaningful increases in liver enzymes. ACH-4471 has improved LDH, hemoglobin, fatigue score, and other measures of response, including PNH clone size.

FDA’s orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

EMA’s orphan designation

The EMA’s orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. It also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to ACH-4471 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

And the European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products has recommended the drug receive orphan status for the same indication in the European Economic Area.

ACH-4471 is a factor D inhibitor being developed by Achillion Pharmaceuticals, Inc.

In April, the company announced the initiation of a phase 2, three-month, dose-ranging trial with ACH-4471 for patients with untreated PNH (NCT03053102).

The primary objective of the trial is to assess the change from baseline in serum lactate dehydrogenase (LDH) levels. Secondary endpoints include changes in hemoglobin, PNH red blood cells, fatigue score (FACIT scale), changes in levels of complement pathway biomarkers such as Bb and factor D, pharmacokinetics, and safety.

The protocol allows for intra-patient dose-escalation. Patients initially receive 100 mg or 150 mg of ACH-4471 three times daily, and doses may be increased during the treatment period.

After patients complete 3 months of treatment and investigators have assessed safety and clinical benefit, patients may be enrolled in the long-term extension trial (NCT03181633).

To date, 200 mg three times daily has been the highest dose of ACH-4471 administered. And Achillion has collected data on 4 patients.

Two of the patients have completed the 3-month trial and entered the long-term extension trial. One patient continues to receive dosing in the 3-month trial, and the fourth patient voluntarily withdrew from the trial on day 41 for reasons unrelated to safety.

Thus far, ACH-4471 has produced clinically meaningful complement inhibition and demonstrated a favorable tolerability profile, with no reports of clinically meaningful increases in liver enzymes. ACH-4471 has improved LDH, hemoglobin, fatigue score, and other measures of response, including PNH clone size.

FDA’s orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

EMA’s orphan designation

The EMA’s orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. It also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The commission typically makes a decision within 30 days of the submission.

Red blood cells

The US Food and Drug Administration (FDA) has approved ferric citrate (Auryxia) to treat iron-deficiency anemia in adults with chronic kidney disease (CKD) who are not on dialysis.

Ferric citrate was originally approved by the FDA in September 2014 for the control of serum phosphorus levels in patients with CKD who require dialysis.

The full prescribing information for the drug is available at www.Auryxia.com.

“We are pleased with the broad indication permitted by the FDA, as a first-line treatment option for adults with iron-deficiency anemia and chronic kidney disease not on dialysis,” said John Neylan, MD, senior vice president and chief medical officer of Keryx Biopharmaceuticals, Inc., the company marketing ferric citrate.

“Physicians and their patients now have a new treatment option to help manage a serious complication of this complex disease.”

The new approval of ferric citrate was based on results from a 24-week, placebo-controlled, phase 3  trial. Results from this trial were published in the Journal of the American Society of Nephrology in January.

The trial enrolled 234 adults with stage 3-5, non-dialysis-dependent CKD and iron-deficiency anemia. Patients had hemoglobin levels between 9.0 g/dL and 11.5 g/dL and were intolerant to or had an inadequate response to prior treatment with oral iron supplements.

The starting dose of ferric citrate was 3 tablets per day, taken with meals. The mean dose was 5 tablets per day. Patients were not allowed to receive any intravenous or oral iron or erythropoiesis-stimulating agents.

Significantly more patients in the ferric citrate arm than the placebo arm had increases in hemoglobin levels of at least 1 g/dL at any point during the trial’s 16-week efficacy period—52.1% (61/117) and 19.1% (22/115), respectively (P<0.001).

Likewise, significantly more patients in the ferric citrate arm than the placebo arm had a sustained increase in hemoglobin of at least 0.75 g/dL over any 4-week period during the trial—48.7% (n=57) and 14.8% (n=17), respectively (P<0.001).

Serious adverse events occurred in 12.0% of patients in the ferric citrate arm and 11.2% of patients in the placebo arm. There were 2 treatment-emergent deaths in the ferric citrate arm (and none in the placebo arm), but they were not considered drug-related.

The most common (≥5%) treatment-emergent adverse events in patients who received ferric citrate were diarrhea (20.5%), constipation (18.8%), discolored feces (14.5%), nausea (11.1%), abdominal pain (6.0%), and hyperkalemia (6.8%).

Red blood cells

The US Food and Drug Administration (FDA) has approved ferric citrate (Auryxia) to treat iron-deficiency anemia in adults with chronic kidney disease (CKD) who are not on dialysis.

Ferric citrate was originally approved by the FDA in September 2014 for the control of serum phosphorus levels in patients with CKD who require dialysis.

The full prescribing information for the drug is available at www.Auryxia.com.

“We are pleased with the broad indication permitted by the FDA, as a first-line treatment option for adults with iron-deficiency anemia and chronic kidney disease not on dialysis,” said John Neylan, MD, senior vice president and chief medical officer of Keryx Biopharmaceuticals, Inc., the company marketing ferric citrate.

“Physicians and their patients now have a new treatment option to help manage a serious complication of this complex disease.”

The new approval of ferric citrate was based on results from a 24-week, placebo-controlled, phase 3  trial. Results from this trial were published in the Journal of the American Society of Nephrology in January.

The trial enrolled 234 adults with stage 3-5, non-dialysis-dependent CKD and iron-deficiency anemia. Patients had hemoglobin levels between 9.0 g/dL and 11.5 g/dL and were intolerant to or had an inadequate response to prior treatment with oral iron supplements.

The starting dose of ferric citrate was 3 tablets per day, taken with meals. The mean dose was 5 tablets per day. Patients were not allowed to receive any intravenous or oral iron or erythropoiesis-stimulating agents.

Significantly more patients in the ferric citrate arm than the placebo arm had increases in hemoglobin levels of at least 1 g/dL at any point during the trial’s 16-week efficacy period—52.1% (61/117) and 19.1% (22/115), respectively (P<0.001).

Likewise, significantly more patients in the ferric citrate arm than the placebo arm had a sustained increase in hemoglobin of at least 0.75 g/dL over any 4-week period during the trial—48.7% (n=57) and 14.8% (n=17), respectively (P<0.001).

Serious adverse events occurred in 12.0% of patients in the ferric citrate arm and 11.2% of patients in the placebo arm. There were 2 treatment-emergent deaths in the ferric citrate arm (and none in the placebo arm), but they were not considered drug-related.

The most common (≥5%) treatment-emergent adverse events in patients who received ferric citrate were diarrhea (20.5%), constipation (18.8%), discolored feces (14.5%), nausea (11.1%), abdominal pain (6.0%), and hyperkalemia (6.8%).

Red blood cells

The US Food and Drug Administration (FDA) has approved ferric citrate (Auryxia) to treat iron-deficiency anemia in adults with chronic kidney disease (CKD) who are not on dialysis.

Ferric citrate was originally approved by the FDA in September 2014 for the control of serum phosphorus levels in patients with CKD who require dialysis.

The full prescribing information for the drug is available at www.Auryxia.com.

“We are pleased with the broad indication permitted by the FDA, as a first-line treatment option for adults with iron-deficiency anemia and chronic kidney disease not on dialysis,” said John Neylan, MD, senior vice president and chief medical officer of Keryx Biopharmaceuticals, Inc., the company marketing ferric citrate.

“Physicians and their patients now have a new treatment option to help manage a serious complication of this complex disease.”

The new approval of ferric citrate was based on results from a 24-week, placebo-controlled, phase 3  trial. Results from this trial were published in the Journal of the American Society of Nephrology in January.

The trial enrolled 234 adults with stage 3-5, non-dialysis-dependent CKD and iron-deficiency anemia. Patients had hemoglobin levels between 9.0 g/dL and 11.5 g/dL and were intolerant to or had an inadequate response to prior treatment with oral iron supplements.

The starting dose of ferric citrate was 3 tablets per day, taken with meals. The mean dose was 5 tablets per day. Patients were not allowed to receive any intravenous or oral iron or erythropoiesis-stimulating agents.

Significantly more patients in the ferric citrate arm than the placebo arm had increases in hemoglobin levels of at least 1 g/dL at any point during the trial’s 16-week efficacy period—52.1% (61/117) and 19.1% (22/115), respectively (P<0.001).

Likewise, significantly more patients in the ferric citrate arm than the placebo arm had a sustained increase in hemoglobin of at least 0.75 g/dL over any 4-week period during the trial—48.7% (n=57) and 14.8% (n=17), respectively (P<0.001).

Serious adverse events occurred in 12.0% of patients in the ferric citrate arm and 11.2% of patients in the placebo arm. There were 2 treatment-emergent deaths in the ferric citrate arm (and none in the placebo arm), but they were not considered drug-related.

The most common (≥5%) treatment-emergent adverse events in patients who received ferric citrate were diarrhea (20.5%), constipation (18.8%), discolored feces (14.5%), nausea (11.1%), abdominal pain (6.0%), and hyperkalemia (6.8%).

Red and white blood cells

The US Food and Drug Administration (FDA) has expanded the approved use of the XW-100 Automated Hematology Analyzer.

The analyzer can now be used at non-traditional laboratory sites by non-medical personnel.

The XW-100 Automated Hematology Analyzer is intended for use in patients age 2 and older who require a whole blood cell count and white blood cell differential.

Test results can be used with other clinical and laboratory findings to provide early alerts of patients with serious conditions, such as severe anemia and agranulocytosis, who require additional testing.

The XW-100 Automated Hematology Analyzer is not intended to diagnose or monitor patients with primary and/or secondary hematologic diseases.

The device works by using a blood sample to classify and quantify 12 hematology parameters, which provides patients with a blood component profile as part of their overall health assessment.

Expanded clearance

The FDA granted the XW-100 Automated Hematology Analyzer a waiver under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The waiver allows the device to be used by a variety of non-traditional laboratory sites, including physicians’ offices, clinics, or other types of healthcare facilities with a CLIA Certificate of Waiver.

The XW-100 Automated Hematology Analyzer was reviewed through the dual submission pathway, a streamlined regulatory pathway for 510(k) marketing clearance and CLIA Waiver by Application.

A 510(k) notification is a premarket submission made by device manufacturers to the FDA to demonstrate that the new device is substantially equivalent to a legally marketed predicate device.

The XW-100 Automated Hematology Analyzer was originally cleared through the 510(k) pathway in 2015 for use at the patient’s point-of-care.

To support the use of this device in CLIA-waived settings with non-medical personnel, the analyzer is now accompanied by simple instructions for operator actions when results are flagged or outside of a specified range.

To further ensure accurate testing in this setting and to eliminate results that are most susceptible to inaccuracy or require additional testing, the number of hematology parameters has been reduced to 12.

The FDA found this modified version of the XW-100 Automated Hematology Analyzer to be substantially equivalent to the 2015 model.

In addition, data submitted by Sysmex America, Inc. (the company marketing the analyzer) demonstrated ease of use and a low risk of false results when the modified XW-100 Automated Hematology Analyzer was used by untrained operators.

The FDA reviewed data from a study conducted on 582 samples collected from patients ages 2 to 92.

In this study, researchers compared XW-100 Automated Hematology Analyzer results collected by non-medical personnel in CLIA-waived settings to results from a hematology analyzer in an accredited clinical laboratory.

Results showed that, by following the manufacturer’s instructions for use, accurate testing can be effectively conducted by untrained personnel.

Red and white blood cells

The US Food and Drug Administration (FDA) has expanded the approved use of the XW-100 Automated Hematology Analyzer.

The analyzer can now be used at non-traditional laboratory sites by non-medical personnel.

The XW-100 Automated Hematology Analyzer is intended for use in patients age 2 and older who require a whole blood cell count and white blood cell differential.

Test results can be used with other clinical and laboratory findings to provide early alerts of patients with serious conditions, such as severe anemia and agranulocytosis, who require additional testing.

The XW-100 Automated Hematology Analyzer is not intended to diagnose or monitor patients with primary and/or secondary hematologic diseases.

The device works by using a blood sample to classify and quantify 12 hematology parameters, which provides patients with a blood component profile as part of their overall health assessment.

Expanded clearance

The FDA granted the XW-100 Automated Hematology Analyzer a waiver under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The waiver allows the device to be used by a variety of non-traditional laboratory sites, including physicians’ offices, clinics, or other types of healthcare facilities with a CLIA Certificate of Waiver.

The XW-100 Automated Hematology Analyzer was reviewed through the dual submission pathway, a streamlined regulatory pathway for 510(k) marketing clearance and CLIA Waiver by Application.

A 510(k) notification is a premarket submission made by device manufacturers to the FDA to demonstrate that the new device is substantially equivalent to a legally marketed predicate device.

The XW-100 Automated Hematology Analyzer was originally cleared through the 510(k) pathway in 2015 for use at the patient’s point-of-care.

To support the use of this device in CLIA-waived settings with non-medical personnel, the analyzer is now accompanied by simple instructions for operator actions when results are flagged or outside of a specified range.

To further ensure accurate testing in this setting and to eliminate results that are most susceptible to inaccuracy or require additional testing, the number of hematology parameters has been reduced to 12.

The FDA found this modified version of the XW-100 Automated Hematology Analyzer to be substantially equivalent to the 2015 model.

In addition, data submitted by Sysmex America, Inc. (the company marketing the analyzer) demonstrated ease of use and a low risk of false results when the modified XW-100 Automated Hematology Analyzer was used by untrained operators.

The FDA reviewed data from a study conducted on 582 samples collected from patients ages 2 to 92.

In this study, researchers compared XW-100 Automated Hematology Analyzer results collected by non-medical personnel in CLIA-waived settings to results from a hematology analyzer in an accredited clinical laboratory.

Results showed that, by following the manufacturer’s instructions for use, accurate testing can be effectively conducted by untrained personnel.

Red and white blood cells

The US Food and Drug Administration (FDA) has expanded the approved use of the XW-100 Automated Hematology Analyzer.

The analyzer can now be used at non-traditional laboratory sites by non-medical personnel.

The XW-100 Automated Hematology Analyzer is intended for use in patients age 2 and older who require a whole blood cell count and white blood cell differential.

Test results can be used with other clinical and laboratory findings to provide early alerts of patients with serious conditions, such as severe anemia and agranulocytosis, who require additional testing.

The XW-100 Automated Hematology Analyzer is not intended to diagnose or monitor patients with primary and/or secondary hematologic diseases.

The device works by using a blood sample to classify and quantify 12 hematology parameters, which provides patients with a blood component profile as part of their overall health assessment.

Expanded clearance

The FDA granted the XW-100 Automated Hematology Analyzer a waiver under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The waiver allows the device to be used by a variety of non-traditional laboratory sites, including physicians’ offices, clinics, or other types of healthcare facilities with a CLIA Certificate of Waiver.

The XW-100 Automated Hematology Analyzer was reviewed through the dual submission pathway, a streamlined regulatory pathway for 510(k) marketing clearance and CLIA Waiver by Application.

A 510(k) notification is a premarket submission made by device manufacturers to the FDA to demonstrate that the new device is substantially equivalent to a legally marketed predicate device.

The XW-100 Automated Hematology Analyzer was originally cleared through the 510(k) pathway in 2015 for use at the patient’s point-of-care.

To support the use of this device in CLIA-waived settings with non-medical personnel, the analyzer is now accompanied by simple instructions for operator actions when results are flagged or outside of a specified range.

To further ensure accurate testing in this setting and to eliminate results that are most susceptible to inaccuracy or require additional testing, the number of hematology parameters has been reduced to 12.

The FDA found this modified version of the XW-100 Automated Hematology Analyzer to be substantially equivalent to the 2015 model.

In addition, data submitted by Sysmex America, Inc. (the company marketing the analyzer) demonstrated ease of use and a low risk of false results when the modified XW-100 Automated Hematology Analyzer was used by untrained operators.

The FDA reviewed data from a study conducted on 582 samples collected from patients ages 2 to 92.

In this study, researchers compared XW-100 Automated Hematology Analyzer results collected by non-medical personnel in CLIA-waived settings to results from a hematology analyzer in an accredited clinical laboratory.

Results showed that, by following the manufacturer’s instructions for use, accurate testing can be effectively conducted by untrained personnel.

For more than a year, NeDina Brocks-Capla avoided one room in her large, brightly colored San Francisco house – the bathroom on the second floor.

“It was really hard to bathe in here, and I found myself not wanting to touch the walls,” she explained. The bathroom is where Ms. Brocks-Capla’s son Kareem Jones died in 2013 at age 36, from sickle cell disease.

It’s not just the loss of her son that upsets Ms. Brocks-Capla; she believes that if Mr. Jones had gotten the proper medical care, he might still be alive today.

Sickle cell disease is an inherited disorder that causes some red blood cells to bend into a crescent shape. The misshapen, inflexible cells clog the blood vessels, preventing blood from circulating oxygen properly, which can cause chronic pain, multiorgan failure, and stroke. About 100,000 people in the United States have sickle cell disease, and most of them are African American.

Patients and experts alike say it’s no surprise then that while life expectancy for almost every major malady is improving, patients with sickle cell disease can expect to die younger than they did 20 years ago. In 1994, life expectancy for sickle cell patients was 42 for men and 48 for women. By 2005, life expectancy had dipped to 38 for men and 42 for women.

Sickle cell disease is “a microcosm of how issues of race, ethnicity and identity come into conflict with issues of health care,” said Keith Wailoo, PhD, a professor at Princeton University who writes about the history of the disease.

It is also an example of the broader discrimination experienced by African Americans in the medical system. Nearly a third report that they have experienced discrimination when going to the doctor, according to a poll by NPR, Robert Wood Johnson Foundation, and Harvard T.H. Chan School of Public Health.

“One of the national crises in health care is the care for adult sickle cell,” said leading researcher and physician Elliott Vichinsky, MD, who started the sickle cell center at UCSF Benioff Children’s Hospital Oakland in 1978. “This group of people can live much longer with the management we have, and they’re dying because we don’t have access to care.”

Indeed, with the proper care, Dr. Vichinsky’s center and the handful of other specialty clinics like it across the country have been able to increase life expectancy for sickle cell patients well into their 60s.

Dr. Vichinsky’s patient Derek Perkins, 45, knows he has already beaten the odds. He sits in an exam room decorated with cartoon characters at Children’s Hospital Oakland, but this is the adult sickle cell clinic. He’s been Dr. Vichinsky’s patient since childhood.

“Without the sickle cell clinic here in Oakland, I don’t know what I would do. I don’t know anywhere else I could go,” Mr. Perkins said.

When Mr. Perkins was 27, he once ended up at a different hospital where doctors misdiagnosed his crisis. He went into a coma and was near death before his mother insisted he be transferred.

“Dr. Vichinsky was able to get me here to Children’s Hospital, and he found out what was wrong and within 18 hours – all I needed was an emergency blood transfusion and I was awake,” Mr. Perkins recalled.

Kareem Jones lived just across the bay from Mr. Perkins, but he had a profoundly different experience.

Mr. Jones’ mother, Ms. Brocks-Capla, said her son received excellent medical care as a child, but once he turned 18 and aged out of his pediatric program, it felt like falling off a cliff. Mr. Jones was sent to a clinic at San Francisco General Hospital, but it was open only for a half-day, one day each week. If he was sick any other day, he had two options: leave a voicemail for a clinic nurse or go to the emergency room. “That’s not comprehensive care – that’s not consistent care for a disease of this type,” said Ms. Brocks-Capla.

Ms. Brocks-Capla is a retired supervisor at a worker’s compensation firm. She knew how to navigate the health care system, but she couldn’t get her son the care he needed. Like most sickle cell patients, Mr. Jones had frequent pain crises. Usually he ended up in the emergency department where, Ms. Brocks-Capla said, the doctors didn’t seem to know much about sickle cell disease.

When she tried to explain her son’s pain to the doctors and nurses, she recalled, “they say have a seat. ‘He can’t have a seat! Can’t you see him?’ ”

Studies have found that sickle cell patients have to wait up to 50% longer for help in the emergency department than do other pain patients. The opioid crisis has made things even worse, Dr. Vichinsky added, as patients in terrible pain are likely to be seen as drug seekers with addiction problems rather than patients in need.

Despite his illness, Mr. Jones fought to have a normal life. He lived with his girlfriend, had a daughter, and worked as much as he could between pain crises. He was an avid San Francisco Giants fan.

For years, he took hydroxyurea, but it had side effects, and after a while Mr. Jones had to stop taking it. “And that was it, because you know there isn’t any other medication out there,” said Ms. Brocks-Capla.

Indeed, hydroxyurea, which the Food and Drug Administration first approved in 1967 as a cancer drug, was the only drug on the market to treat sickle cell during Mr. Jones’ lifetime. In July, the FDA approved a second drug, Endari (L-glutamine oral powder), specifically to treat patients with sickle cell disease.

Funding by the federal government and private foundations for the disease pales in comparison to other disorders. Cystic fibrosis offers a good comparison. It is another inherited disorder that requires complex care and most often occurs in Caucasians. Cystic fibrosis gets 7-11 times more funding per patient than does sickle cell disease, according to a 2013 study in the journal Blood. From 2010 to 2013 alone, the FDA approved five new drugs for the treatment of cystic fibrosis.

“There’s no question in my mind that class and color are major factors in impairing their survival. Without question,” Dr. Vichinsky said of sickle cell patients. “The death rate is increasing. The quality of care is going down.”

Without a new medication, Mr. Jones got progressively worse. At 36, his kidneys began to fail, and he had to go on dialysis. He ended up in the hospital, with the worst pain of his life. The doctors stabilized him and gave him pain meds but did not diagnose the underlying cause of the crisis. He was released to his mother’s care, still in incredible pain.

At home, Ms. Brocks-Capla ran him a warm bath to try to soothe his pain and went downstairs to get him a change of clothes. As she came back up the stairs, she heard loud banging against the bathroom walls.

“So I run into the bathroom and he’s having a seizure. And I didn’t know what to do. I was like, ‘Oh come on, come on. Don’t do this. Don’t do this to me.’ ”

She called 911. The paramedics came but couldn’t revive him. “He died here with me,” she said.

It turned out Mr. Jones had a series of small strokes. His organs were in failure, something Ms. Brocks-Capla said the hospital missed. She believes his death could have been prevented with consistent care – the kind he got as a child. Dr. Vichinsky thinks she is probably right.

“I would say 40% or more of the deaths I’ve had recently have been preventable – I mean totally preventable,” he said, but he got to the cases too late. “It makes me so angry. I’ve spent my life trying to help these people, and the harder part is you can change this – this isn’t a knowledge issue. It’s an access issue.”

Dr. Vichinsky’s center and others like it have made major advances in screening patients for the early signs of organ failure and intervening to prevent premature death. Patients at these clinics live 2 decades longer than the average sickle cell patient.

Good care for sickle cell requires time and training for physicians, but it often doesn’t pay well, because many patients are on Medicaid or other government insurance programs. The result is that most adult sickle cell patients still struggle even to access treatments that have been around for decades, Dr. Vichinsky said.

The phenomenon is nothing new — the disease that used to be known as sickle cell anemia has had a long and sordid past. It was first identified in 1910 and helped launch the field of molecular biology. But most of the research was used to study science rather than improving care for sickle cell patients, Dr. Vichinsky said.

In the 1960s and 1970s, sickle cell became a lightning rod for the civil rights movement. At the time, the average patient died before age 20. The Black Panther Party took up the cause and began testing people at its “survival conferences” across the country.

“I’m sure we tested over four-and-a-half-thousand people for sickle cell anemia last night – and I think that the voter registration is running neck and neck with it,” Black Panther Party Chairman Bobby Seale told news crews at an event in Oakland in 1972.

The movement grew, and Washington listened. “It is a sad and shameful fact that the causes of this disease have been largely neglected throughout our history,” President Richard Nixon told Congress in 1971. “We cannot rewrite this record of neglect, but we can reverse it. To this end, this administration is increasing its budget for research and treatment of sickle cell disease.”

For a while, funding did increase, newborn screening took hold, and by the 1990s, life expectancy had doubled, with patients living into their 40s. But over time, funding waned, clinics closed, and life expectancy started dropping again.

Dr. Vichinsky pushes against that trend for patients like Derek Perkins. The father of four looks healthy and robust, but like most sickle cell patients, he has episodes of extreme pain and has problems with his kidneys, heart, hips, and breathing. Keeping him thriving requires regular checkups and constant monitoring for potential problems.

“The program Dr. Vichinsky is running here, I feel I owe my life to [it],” said Mr. Perkins. “If it wasn’t for him and the things that he did for me, my family wouldn’t have me.”
 

Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation. KHN’s coverage of children’s health care issues is supported in part by a grant from The Heising-Simons Foundation.

For more than a year, NeDina Brocks-Capla avoided one room in her large, brightly colored San Francisco house – the bathroom on the second floor.

“It was really hard to bathe in here, and I found myself not wanting to touch the walls,” she explained. The bathroom is where Ms. Brocks-Capla’s son Kareem Jones died in 2013 at age 36, from sickle cell disease.

It’s not just the loss of her son that upsets Ms. Brocks-Capla; she believes that if Mr. Jones had gotten the proper medical care, he might still be alive today.

Sickle cell disease is an inherited disorder that causes some red blood cells to bend into a crescent shape. The misshapen, inflexible cells clog the blood vessels, preventing blood from circulating oxygen properly, which can cause chronic pain, multiorgan failure, and stroke. About 100,000 people in the United States have sickle cell disease, and most of them are African American.

Patients and experts alike say it’s no surprise then that while life expectancy for almost every major malady is improving, patients with sickle cell disease can expect to die younger than they did 20 years ago. In 1994, life expectancy for sickle cell patients was 42 for men and 48 for women. By 2005, life expectancy had dipped to 38 for men and 42 for women.

Sickle cell disease is “a microcosm of how issues of race, ethnicity and identity come into conflict with issues of health care,” said Keith Wailoo, PhD, a professor at Princeton University who writes about the history of the disease.

It is also an example of the broader discrimination experienced by African Americans in the medical system. Nearly a third report that they have experienced discrimination when going to the doctor, according to a poll by NPR, Robert Wood Johnson Foundation, and Harvard T.H. Chan School of Public Health.

“One of the national crises in health care is the care for adult sickle cell,” said leading researcher and physician Elliott Vichinsky, MD, who started the sickle cell center at UCSF Benioff Children’s Hospital Oakland in 1978. “This group of people can live much longer with the management we have, and they’re dying because we don’t have access to care.”

Indeed, with the proper care, Dr. Vichinsky’s center and the handful of other specialty clinics like it across the country have been able to increase life expectancy for sickle cell patients well into their 60s.

Dr. Vichinsky’s patient Derek Perkins, 45, knows he has already beaten the odds. He sits in an exam room decorated with cartoon characters at Children’s Hospital Oakland, but this is the adult sickle cell clinic. He’s been Dr. Vichinsky’s patient since childhood.

“Without the sickle cell clinic here in Oakland, I don’t know what I would do. I don’t know anywhere else I could go,” Mr. Perkins said.

When Mr. Perkins was 27, he once ended up at a different hospital where doctors misdiagnosed his crisis. He went into a coma and was near death before his mother insisted he be transferred.

“Dr. Vichinsky was able to get me here to Children’s Hospital, and he found out what was wrong and within 18 hours – all I needed was an emergency blood transfusion and I was awake,” Mr. Perkins recalled.

Kareem Jones lived just across the bay from Mr. Perkins, but he had a profoundly different experience.

Mr. Jones’ mother, Ms. Brocks-Capla, said her son received excellent medical care as a child, but once he turned 18 and aged out of his pediatric program, it felt like falling off a cliff. Mr. Jones was sent to a clinic at San Francisco General Hospital, but it was open only for a half-day, one day each week. If he was sick any other day, he had two options: leave a voicemail for a clinic nurse or go to the emergency room. “That’s not comprehensive care – that’s not consistent care for a disease of this type,” said Ms. Brocks-Capla.

Ms. Brocks-Capla is a retired supervisor at a worker’s compensation firm. She knew how to navigate the health care system, but she couldn’t get her son the care he needed. Like most sickle cell patients, Mr. Jones had frequent pain crises. Usually he ended up in the emergency department where, Ms. Brocks-Capla said, the doctors didn’t seem to know much about sickle cell disease.

When she tried to explain her son’s pain to the doctors and nurses, she recalled, “they say have a seat. ‘He can’t have a seat! Can’t you see him?’ ”

Studies have found that sickle cell patients have to wait up to 50% longer for help in the emergency department than do other pain patients. The opioid crisis has made things even worse, Dr. Vichinsky added, as patients in terrible pain are likely to be seen as drug seekers with addiction problems rather than patients in need.

Despite his illness, Mr. Jones fought to have a normal life. He lived with his girlfriend, had a daughter, and worked as much as he could between pain crises. He was an avid San Francisco Giants fan.

For years, he took hydroxyurea, but it had side effects, and after a while Mr. Jones had to stop taking it. “And that was it, because you know there isn’t any other medication out there,” said Ms. Brocks-Capla.

Indeed, hydroxyurea, which the Food and Drug Administration first approved in 1967 as a cancer drug, was the only drug on the market to treat sickle cell during Mr. Jones’ lifetime. In July, the FDA approved a second drug, Endari (L-glutamine oral powder), specifically to treat patients with sickle cell disease.

Funding by the federal government and private foundations for the disease pales in comparison to other disorders. Cystic fibrosis offers a good comparison. It is another inherited disorder that requires complex care and most often occurs in Caucasians. Cystic fibrosis gets 7-11 times more funding per patient than does sickle cell disease, according to a 2013 study in the journal Blood. From 2010 to 2013 alone, the FDA approved five new drugs for the treatment of cystic fibrosis.

“There’s no question in my mind that class and color are major factors in impairing their survival. Without question,” Dr. Vichinsky said of sickle cell patients. “The death rate is increasing. The quality of care is going down.”

Without a new medication, Mr. Jones got progressively worse. At 36, his kidneys began to fail, and he had to go on dialysis. He ended up in the hospital, with the worst pain of his life. The doctors stabilized him and gave him pain meds but did not diagnose the underlying cause of the crisis. He was released to his mother’s care, still in incredible pain.

At home, Ms. Brocks-Capla ran him a warm bath to try to soothe his pain and went downstairs to get him a change of clothes. As she came back up the stairs, she heard loud banging against the bathroom walls.

“So I run into the bathroom and he’s having a seizure. And I didn’t know what to do. I was like, ‘Oh come on, come on. Don’t do this. Don’t do this to me.’ ”

She called 911. The paramedics came but couldn’t revive him. “He died here with me,” she said.

It turned out Mr. Jones had a series of small strokes. His organs were in failure, something Ms. Brocks-Capla said the hospital missed. She believes his death could have been prevented with consistent care – the kind he got as a child. Dr. Vichinsky thinks she is probably right.

“I would say 40% or more of the deaths I’ve had recently have been preventable – I mean totally preventable,” he said, but he got to the cases too late. “It makes me so angry. I’ve spent my life trying to help these people, and the harder part is you can change this – this isn’t a knowledge issue. It’s an access issue.”

Dr. Vichinsky’s center and others like it have made major advances in screening patients for the early signs of organ failure and intervening to prevent premature death. Patients at these clinics live 2 decades longer than the average sickle cell patient.

Good care for sickle cell requires time and training for physicians, but it often doesn’t pay well, because many patients are on Medicaid or other government insurance programs. The result is that most adult sickle cell patients still struggle even to access treatments that have been around for decades, Dr. Vichinsky said.

The phenomenon is nothing new — the disease that used to be known as sickle cell anemia has had a long and sordid past. It was first identified in 1910 and helped launch the field of molecular biology. But most of the research was used to study science rather than improving care for sickle cell patients, Dr. Vichinsky said.

In the 1960s and 1970s, sickle cell became a lightning rod for the civil rights movement. At the time, the average patient died before age 20. The Black Panther Party took up the cause and began testing people at its “survival conferences” across the country.

“I’m sure we tested over four-and-a-half-thousand people for sickle cell anemia last night – and I think that the voter registration is running neck and neck with it,” Black Panther Party Chairman Bobby Seale told news crews at an event in Oakland in 1972.

The movement grew, and Washington listened. “It is a sad and shameful fact that the causes of this disease have been largely neglected throughout our history,” President Richard Nixon told Congress in 1971. “We cannot rewrite this record of neglect, but we can reverse it. To this end, this administration is increasing its budget for research and treatment of sickle cell disease.”

For a while, funding did increase, newborn screening took hold, and by the 1990s, life expectancy had doubled, with patients living into their 40s. But over time, funding waned, clinics closed, and life expectancy started dropping again.

Dr. Vichinsky pushes against that trend for patients like Derek Perkins. The father of four looks healthy and robust, but like most sickle cell patients, he has episodes of extreme pain and has problems with his kidneys, heart, hips, and breathing. Keeping him thriving requires regular checkups and constant monitoring for potential problems.

“The program Dr. Vichinsky is running here, I feel I owe my life to [it],” said Mr. Perkins. “If it wasn’t for him and the things that he did for me, my family wouldn’t have me.”
 

Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation. KHN’s coverage of children’s health care issues is supported in part by a grant from The Heising-Simons Foundation.

For more than a year, NeDina Brocks-Capla avoided one room in her large, brightly colored San Francisco house – the bathroom on the second floor.

“It was really hard to bathe in here, and I found myself not wanting to touch the walls,” she explained. The bathroom is where Ms. Brocks-Capla’s son Kareem Jones died in 2013 at age 36, from sickle cell disease.

It’s not just the loss of her son that upsets Ms. Brocks-Capla; she believes that if Mr. Jones had gotten the proper medical care, he might still be alive today.

Sickle cell disease is an inherited disorder that causes some red blood cells to bend into a crescent shape. The misshapen, inflexible cells clog the blood vessels, preventing blood from circulating oxygen properly, which can cause chronic pain, multiorgan failure, and stroke. About 100,000 people in the United States have sickle cell disease, and most of them are African American.

Patients and experts alike say it’s no surprise then that while life expectancy for almost every major malady is improving, patients with sickle cell disease can expect to die younger than they did 20 years ago. In 1994, life expectancy for sickle cell patients was 42 for men and 48 for women. By 2005, life expectancy had dipped to 38 for men and 42 for women.

Sickle cell disease is “a microcosm of how issues of race, ethnicity and identity come into conflict with issues of health care,” said Keith Wailoo, PhD, a professor at Princeton University who writes about the history of the disease.

It is also an example of the broader discrimination experienced by African Americans in the medical system. Nearly a third report that they have experienced discrimination when going to the doctor, according to a poll by NPR, Robert Wood Johnson Foundation, and Harvard T.H. Chan School of Public Health.

“One of the national crises in health care is the care for adult sickle cell,” said leading researcher and physician Elliott Vichinsky, MD, who started the sickle cell center at UCSF Benioff Children’s Hospital Oakland in 1978. “This group of people can live much longer with the management we have, and they’re dying because we don’t have access to care.”

Indeed, with the proper care, Dr. Vichinsky’s center and the handful of other specialty clinics like it across the country have been able to increase life expectancy for sickle cell patients well into their 60s.

Dr. Vichinsky’s patient Derek Perkins, 45, knows he has already beaten the odds. He sits in an exam room decorated with cartoon characters at Children’s Hospital Oakland, but this is the adult sickle cell clinic. He’s been Dr. Vichinsky’s patient since childhood.

“Without the sickle cell clinic here in Oakland, I don’t know what I would do. I don’t know anywhere else I could go,” Mr. Perkins said.

When Mr. Perkins was 27, he once ended up at a different hospital where doctors misdiagnosed his crisis. He went into a coma and was near death before his mother insisted he be transferred.

“Dr. Vichinsky was able to get me here to Children’s Hospital, and he found out what was wrong and within 18 hours – all I needed was an emergency blood transfusion and I was awake,” Mr. Perkins recalled.

Kareem Jones lived just across the bay from Mr. Perkins, but he had a profoundly different experience.

Mr. Jones’ mother, Ms. Brocks-Capla, said her son received excellent medical care as a child, but once he turned 18 and aged out of his pediatric program, it felt like falling off a cliff. Mr. Jones was sent to a clinic at San Francisco General Hospital, but it was open only for a half-day, one day each week. If he was sick any other day, he had two options: leave a voicemail for a clinic nurse or go to the emergency room. “That’s not comprehensive care – that’s not consistent care for a disease of this type,” said Ms. Brocks-Capla.

Ms. Brocks-Capla is a retired supervisor at a worker’s compensation firm. She knew how to navigate the health care system, but she couldn’t get her son the care he needed. Like most sickle cell patients, Mr. Jones had frequent pain crises. Usually he ended up in the emergency department where, Ms. Brocks-Capla said, the doctors didn’t seem to know much about sickle cell disease.

When she tried to explain her son’s pain to the doctors and nurses, she recalled, “they say have a seat. ‘He can’t have a seat! Can’t you see him?’ ”

Studies have found that sickle cell patients have to wait up to 50% longer for help in the emergency department than do other pain patients. The opioid crisis has made things even worse, Dr. Vichinsky added, as patients in terrible pain are likely to be seen as drug seekers with addiction problems rather than patients in need.

Despite his illness, Mr. Jones fought to have a normal life. He lived with his girlfriend, had a daughter, and worked as much as he could between pain crises. He was an avid San Francisco Giants fan.

For years, he took hydroxyurea, but it had side effects, and after a while Mr. Jones had to stop taking it. “And that was it, because you know there isn’t any other medication out there,” said Ms. Brocks-Capla.

Indeed, hydroxyurea, which the Food and Drug Administration first approved in 1967 as a cancer drug, was the only drug on the market to treat sickle cell during Mr. Jones’ lifetime. In July, the FDA approved a second drug, Endari (L-glutamine oral powder), specifically to treat patients with sickle cell disease.

Funding by the federal government and private foundations for the disease pales in comparison to other disorders. Cystic fibrosis offers a good comparison. It is another inherited disorder that requires complex care and most often occurs in Caucasians. Cystic fibrosis gets 7-11 times more funding per patient than does sickle cell disease, according to a 2013 study in the journal Blood. From 2010 to 2013 alone, the FDA approved five new drugs for the treatment of cystic fibrosis.

“There’s no question in my mind that class and color are major factors in impairing their survival. Without question,” Dr. Vichinsky said of sickle cell patients. “The death rate is increasing. The quality of care is going down.”

Without a new medication, Mr. Jones got progressively worse. At 36, his kidneys began to fail, and he had to go on dialysis. He ended up in the hospital, with the worst pain of his life. The doctors stabilized him and gave him pain meds but did not diagnose the underlying cause of the crisis. He was released to his mother’s care, still in incredible pain.

At home, Ms. Brocks-Capla ran him a warm bath to try to soothe his pain and went downstairs to get him a change of clothes. As she came back up the stairs, she heard loud banging against the bathroom walls.

“So I run into the bathroom and he’s having a seizure. And I didn’t know what to do. I was like, ‘Oh come on, come on. Don’t do this. Don’t do this to me.’ ”

She called 911. The paramedics came but couldn’t revive him. “He died here with me,” she said.

It turned out Mr. Jones had a series of small strokes. His organs were in failure, something Ms. Brocks-Capla said the hospital missed. She believes his death could have been prevented with consistent care – the kind he got as a child. Dr. Vichinsky thinks she is probably right.

“I would say 40% or more of the deaths I’ve had recently have been preventable – I mean totally preventable,” he said, but he got to the cases too late. “It makes me so angry. I’ve spent my life trying to help these people, and the harder part is you can change this – this isn’t a knowledge issue. It’s an access issue.”

Dr. Vichinsky’s center and others like it have made major advances in screening patients for the early signs of organ failure and intervening to prevent premature death. Patients at these clinics live 2 decades longer than the average sickle cell patient.

Good care for sickle cell requires time and training for physicians, but it often doesn’t pay well, because many patients are on Medicaid or other government insurance programs. The result is that most adult sickle cell patients still struggle even to access treatments that have been around for decades, Dr. Vichinsky said.

The phenomenon is nothing new — the disease that used to be known as sickle cell anemia has had a long and sordid past. It was first identified in 1910 and helped launch the field of molecular biology. But most of the research was used to study science rather than improving care for sickle cell patients, Dr. Vichinsky said.

In the 1960s and 1970s, sickle cell became a lightning rod for the civil rights movement. At the time, the average patient died before age 20. The Black Panther Party took up the cause and began testing people at its “survival conferences” across the country.

“I’m sure we tested over four-and-a-half-thousand people for sickle cell anemia last night – and I think that the voter registration is running neck and neck with it,” Black Panther Party Chairman Bobby Seale told news crews at an event in Oakland in 1972.

The movement grew, and Washington listened. “It is a sad and shameful fact that the causes of this disease have been largely neglected throughout our history,” President Richard Nixon told Congress in 1971. “We cannot rewrite this record of neglect, but we can reverse it. To this end, this administration is increasing its budget for research and treatment of sickle cell disease.”

For a while, funding did increase, newborn screening took hold, and by the 1990s, life expectancy had doubled, with patients living into their 40s. But over time, funding waned, clinics closed, and life expectancy started dropping again.

Dr. Vichinsky pushes against that trend for patients like Derek Perkins. The father of four looks healthy and robust, but like most sickle cell patients, he has episodes of extreme pain and has problems with his kidneys, heart, hips, and breathing. Keeping him thriving requires regular checkups and constant monitoring for potential problems.

“The program Dr. Vichinsky is running here, I feel I owe my life to [it],” said Mr. Perkins. “If it wasn’t for him and the things that he did for me, my family wouldn’t have me.”
 

Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation. KHN’s coverage of children’s health care issues is supported in part by a grant from The Heising-Simons Foundation.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.

The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).

Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.

Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.

Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.

Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.

The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.

As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.

Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.

The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).

Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.

Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.

Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.

Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.

The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.

As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.

Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.

The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).

Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.

Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.

Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.

Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.

The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.

As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.

Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Image from PLOS ONE

Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.

In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.

However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.

On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.

These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.

The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.

Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.

In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).

Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m² on day 1, then 10 mg/m² on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.

Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:

• Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.

Overall results

Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).

However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).

In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).

In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).

Role of conditioning, ALC

The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.

For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).

For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).

For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).

The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 10⁹/L, compared to less than 35% of patients who received busulfan-based conditioning.

ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 10⁹/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.

ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.

Image from PLOS ONE

Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.

In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.

However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.

On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.

These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.

The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.

Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.

In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).

Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m² on day 1, then 10 mg/m² on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.

Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:

• Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.

Overall results

Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).

However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).

In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).

In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).

Role of conditioning, ALC

The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.

For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).

For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).

For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).

The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 10⁹/L, compared to less than 35% of patients who received busulfan-based conditioning.

ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 10⁹/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.

ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.

Image from PLOS ONE

Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.

In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.

However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.

On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.

These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.

The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.

Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.

In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).

Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m² on day 1, then 10 mg/m² on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.

Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:

• Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
• Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.

Overall results

Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).

However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).

In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).

In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).

Role of conditioning, ALC

The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.

For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).

For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).

For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).

The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 10⁹/L, compared to less than 35% of patients who received busulfan-based conditioning.

ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 10⁹/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.

ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.

Image by Betty Pace

Scientists say they have developed an automated system that can identify shapes of red blood cells (RBCs).

The team found their system could classify sickled RBCs “with high accuracy,” which suggests it could be used to help monitor patients with sickle cell disease.

“We have developed the first deep learning tool that can automatically identify and classify red blood cell alteration, hence providing direct quantitative evidence of the severity of the disease,” said George Karniadakis, PhD, of Brown University in Providence, Rhode Island.

Dr Karniadakis and his colleagues described their tool in PLOS Computational Biology.

The researchers wanted to automate the process of identifying RBC shape. So they developed a computational framework that employs a machine-learning tool known as a deep convolutional neural network (CNN).

The framework uses 3 steps to classify the shapes of RBCs in microscopic images of blood.

First, it distinguishes RBCs from the background of each image and from each other. Then, for each cell detected, it zooms in or out until all cell images are a uniform size. Finally, it uses deep CNNs to categorize RBCs by shape.

The researchers validated their new tool using 7000 microscopy images from 8 patients with sickle cell disease. The method successfully classified RBC shape for both oxygenated and deoxygenated cells.

The researchers plan to further improve their deep CNN tool and test it in other diseases that alter the shape and size of RBCs, such as diabetes and HIV. They also plan to explore its usefulness in characterizing cancer cells.

Image by Betty Pace

Scientists say they have developed an automated system that can identify shapes of red blood cells (RBCs).

The team found their system could classify sickled RBCs “with high accuracy,” which suggests it could be used to help monitor patients with sickle cell disease.

“We have developed the first deep learning tool that can automatically identify and classify red blood cell alteration, hence providing direct quantitative evidence of the severity of the disease,” said George Karniadakis, PhD, of Brown University in Providence, Rhode Island.

Dr Karniadakis and his colleagues described their tool in PLOS Computational Biology.

The researchers wanted to automate the process of identifying RBC shape. So they developed a computational framework that employs a machine-learning tool known as a deep convolutional neural network (CNN).

The framework uses 3 steps to classify the shapes of RBCs in microscopic images of blood.

First, it distinguishes RBCs from the background of each image and from each other. Then, for each cell detected, it zooms in or out until all cell images are a uniform size. Finally, it uses deep CNNs to categorize RBCs by shape.

The researchers validated their new tool using 7000 microscopy images from 8 patients with sickle cell disease. The method successfully classified RBC shape for both oxygenated and deoxygenated cells.

The researchers plan to further improve their deep CNN tool and test it in other diseases that alter the shape and size of RBCs, such as diabetes and HIV. They also plan to explore its usefulness in characterizing cancer cells.

Image by Betty Pace

Scientists say they have developed an automated system that can identify shapes of red blood cells (RBCs).

The team found their system could classify sickled RBCs “with high accuracy,” which suggests it could be used to help monitor patients with sickle cell disease.

“We have developed the first deep learning tool that can automatically identify and classify red blood cell alteration, hence providing direct quantitative evidence of the severity of the disease,” said George Karniadakis, PhD, of Brown University in Providence, Rhode Island.

Dr Karniadakis and his colleagues described their tool in PLOS Computational Biology.

The researchers wanted to automate the process of identifying RBC shape. So they developed a computational framework that employs a machine-learning tool known as a deep convolutional neural network (CNN).

The framework uses 3 steps to classify the shapes of RBCs in microscopic images of blood.

First, it distinguishes RBCs from the background of each image and from each other. Then, for each cell detected, it zooms in or out until all cell images are a uniform size. Finally, it uses deep CNNs to categorize RBCs by shape.

The researchers validated their new tool using 7000 microscopy images from 8 patients with sickle cell disease. The method successfully classified RBC shape for both oxygenated and deoxygenated cells.

The researchers plan to further improve their deep CNN tool and test it in other diseases that alter the shape and size of RBCs, such as diabetes and HIV. They also plan to explore its usefulness in characterizing cancer cells.