AML

The Food and Drug Administration has granted orphan drug designation to ASLAN003 as a treatment for acute myeloid leukemia (AML).

ASLAN003 is a small molecule inhibitor of the human dihydroorotate dehydrogenase (DHODH) enzyme. This second-generation DHODH inhibitor is being developed by Aslan Pharmaceuticals. The company is currently conducting a phase 2 trial (NCT03451084) of ASLAN003 in patients with newly diagnosed or relapsed/refractory AML. Aslan expects to report interim data from this trial in the second half of 2018.

Aslan has already completed a phase 1 trial (NCT01992367) of ASLAN003 in healthy volunteers. The results suggested that ASLAN003 has an “excellent” pharmacokinetic profile, according to Aslan, and the drug was considered well tolerated in the volunteers.

ASLAN003 has also demonstrated “potent” inhibition of DHODH, according to the drug sponsor. In fact, the company said the binding affinity of ASLAN003 to DHODH has proven to be up to two orders of magnitude stronger than first-generation DHODH inhibitors, such as leflunomide and teriflunomide, but it has less toxicity.

In addition, ASLAN003 has been shown to differentiate blast cells into granulocytes in AML cell lines that do not respond to all-trans retinoic acid. These results were published in Cell in 2016.

The Food and Drug Administration has granted orphan drug designation to ASLAN003 as a treatment for acute myeloid leukemia (AML).

ASLAN003 is a small molecule inhibitor of the human dihydroorotate dehydrogenase (DHODH) enzyme. This second-generation DHODH inhibitor is being developed by Aslan Pharmaceuticals. The company is currently conducting a phase 2 trial (NCT03451084) of ASLAN003 in patients with newly diagnosed or relapsed/refractory AML. Aslan expects to report interim data from this trial in the second half of 2018.

Aslan has already completed a phase 1 trial (NCT01992367) of ASLAN003 in healthy volunteers. The results suggested that ASLAN003 has an “excellent” pharmacokinetic profile, according to Aslan, and the drug was considered well tolerated in the volunteers.

ASLAN003 has also demonstrated “potent” inhibition of DHODH, according to the drug sponsor. In fact, the company said the binding affinity of ASLAN003 to DHODH has proven to be up to two orders of magnitude stronger than first-generation DHODH inhibitors, such as leflunomide and teriflunomide, but it has less toxicity.

In addition, ASLAN003 has been shown to differentiate blast cells into granulocytes in AML cell lines that do not respond to all-trans retinoic acid. These results were published in Cell in 2016.

The Food and Drug Administration has granted orphan drug designation to ASLAN003 as a treatment for acute myeloid leukemia (AML).

ASLAN003 is a small molecule inhibitor of the human dihydroorotate dehydrogenase (DHODH) enzyme. This second-generation DHODH inhibitor is being developed by Aslan Pharmaceuticals. The company is currently conducting a phase 2 trial (NCT03451084) of ASLAN003 in patients with newly diagnosed or relapsed/refractory AML. Aslan expects to report interim data from this trial in the second half of 2018.

Aslan has already completed a phase 1 trial (NCT01992367) of ASLAN003 in healthy volunteers. The results suggested that ASLAN003 has an “excellent” pharmacokinetic profile, according to Aslan, and the drug was considered well tolerated in the volunteers.

ASLAN003 has also demonstrated “potent” inhibition of DHODH, according to the drug sponsor. In fact, the company said the binding affinity of ASLAN003 to DHODH has proven to be up to two orders of magnitude stronger than first-generation DHODH inhibitors, such as leflunomide and teriflunomide, but it has less toxicity.

In addition, ASLAN003 has been shown to differentiate blast cells into granulocytes in AML cell lines that do not respond to all-trans retinoic acid. These results were published in Cell in 2016.

Photo by Bill Branson

Socioeconomic status (SES) may explain some racial/ethnic disparities in childhood cancer survival, according to new research.

The study showed that whites had a significant survival advantage over blacks and Hispanics for several childhood cancers.

SES significantly mediated the association between race/ethnicity and survival for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), neuroblastoma, and non-Hodgkin lymphoma (NHL).

Rebecca Kehm, PhD, of Columbia University in New York, New York, and her colleagues reported these findings in Cancer alongside a related editorial.

The researchers examined population-based cancer survival data from the Surveillance, Epidemiology, and End Results database.

The team collected information on 31,866 patients, ages 0 to 19, who were diagnosed with cancer between 2000 and 2011.

Survival differences by race/ethnicity

The researchers found that whites had a significant survival advantage over blacks for the cancers listed in the following table.

In addition, whites had a significant survival advantage over Hispanics for the following cancers.

Impact of SES

SES significantly mediated the association between race/ethnicity and survival for ALL, AML, neuroblastoma, and NHL but not for Hodgkin lymphoma or other cancers.

For black versus white patients, SES reduced the original association between race/ethnicity and survival by:

• 44% for ALL
• 28% for AML
• 49% for neuroblastoma
• 34% for NHL.

For Hispanics versus whites, SES reduced the original association between race/ethnicity and survival by:

• 31% for ALL
• 73% for AML
• 48% for neuroblastoma
• 28% for NHL.

“These findings provide insight for future intervention efforts aimed at closing the survival gap,” Dr Kehm said.

“For cancers in which socioeconomic status is a key factor in explaining racial and ethnic survival disparities, behavioral and supportive interventions that address social and economic barriers to effective care are warranted. However, for cancers in which survival is less influenced by socioeconomic status, more research is needed on underlying differences in tumor biology and drug processing.”

This research was supported by a grant from the National Institutes of Health, and the study’s authors made no disclosures.

Photo by Bill Branson

Socioeconomic status (SES) may explain some racial/ethnic disparities in childhood cancer survival, according to new research.

The study showed that whites had a significant survival advantage over blacks and Hispanics for several childhood cancers.

SES significantly mediated the association between race/ethnicity and survival for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), neuroblastoma, and non-Hodgkin lymphoma (NHL).

Rebecca Kehm, PhD, of Columbia University in New York, New York, and her colleagues reported these findings in Cancer alongside a related editorial.

The researchers examined population-based cancer survival data from the Surveillance, Epidemiology, and End Results database.

The team collected information on 31,866 patients, ages 0 to 19, who were diagnosed with cancer between 2000 and 2011.

Survival differences by race/ethnicity

The researchers found that whites had a significant survival advantage over blacks for the cancers listed in the following table.

In addition, whites had a significant survival advantage over Hispanics for the following cancers.

Impact of SES

SES significantly mediated the association between race/ethnicity and survival for ALL, AML, neuroblastoma, and NHL but not for Hodgkin lymphoma or other cancers.

For black versus white patients, SES reduced the original association between race/ethnicity and survival by:

• 44% for ALL
• 28% for AML
• 49% for neuroblastoma
• 34% for NHL.

For Hispanics versus whites, SES reduced the original association between race/ethnicity and survival by:

• 31% for ALL
• 73% for AML
• 48% for neuroblastoma
• 28% for NHL.

“These findings provide insight for future intervention efforts aimed at closing the survival gap,” Dr Kehm said.

“For cancers in which socioeconomic status is a key factor in explaining racial and ethnic survival disparities, behavioral and supportive interventions that address social and economic barriers to effective care are warranted. However, for cancers in which survival is less influenced by socioeconomic status, more research is needed on underlying differences in tumor biology and drug processing.”

This research was supported by a grant from the National Institutes of Health, and the study’s authors made no disclosures.

Photo by Bill Branson

Socioeconomic status (SES) may explain some racial/ethnic disparities in childhood cancer survival, according to new research.

The study showed that whites had a significant survival advantage over blacks and Hispanics for several childhood cancers.

SES significantly mediated the association between race/ethnicity and survival for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), neuroblastoma, and non-Hodgkin lymphoma (NHL).

Rebecca Kehm, PhD, of Columbia University in New York, New York, and her colleagues reported these findings in Cancer alongside a related editorial.

The researchers examined population-based cancer survival data from the Surveillance, Epidemiology, and End Results database.

The team collected information on 31,866 patients, ages 0 to 19, who were diagnosed with cancer between 2000 and 2011.

Survival differences by race/ethnicity

The researchers found that whites had a significant survival advantage over blacks for the cancers listed in the following table.

In addition, whites had a significant survival advantage over Hispanics for the following cancers.

Impact of SES

SES significantly mediated the association between race/ethnicity and survival for ALL, AML, neuroblastoma, and NHL but not for Hodgkin lymphoma or other cancers.

For black versus white patients, SES reduced the original association between race/ethnicity and survival by:

• 44% for ALL
• 28% for AML
• 49% for neuroblastoma
• 34% for NHL.

For Hispanics versus whites, SES reduced the original association between race/ethnicity and survival by:

• 31% for ALL
• 73% for AML
• 48% for neuroblastoma
• 28% for NHL.

“These findings provide insight for future intervention efforts aimed at closing the survival gap,” Dr Kehm said.

“For cancers in which socioeconomic status is a key factor in explaining racial and ethnic survival disparities, behavioral and supportive interventions that address social and economic barriers to effective care are warranted. However, for cancers in which survival is less influenced by socioeconomic status, more research is needed on underlying differences in tumor biology and drug processing.”

This research was supported by a grant from the National Institutes of Health, and the study’s authors made no disclosures.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to ASLAN003 as a treatment for acute myeloid leukemia (AML).

ASLAN003 is a small molecule inhibitor of the human dihydroorotate dehydrogenase (DHODH) enzyme.

This second-generation DHODH inhibitor is being developed by ASLAN Pharmaceuticals.

The company is currently conducting a phase 2 trial (NCT03451084) of ASLAN003 in patients with newly diagnosed or relapsed/refractory AML.

The goals of this trial are to determine the optimum dose of ASLAN003 as monotherapy and assess the drug’s efficacy by overall complete remission rate. ASLAN expects to report interim data from this trial in the second half of this year.

ASLAN has already completed a phase 1 trial (NCT01992367) of ASLAN003 in healthy volunteers.

Results suggested that ASLAN003 has an “excellent” pharmacokinetic profile, according to ASLAN, and the drug was considered well tolerated in the volunteers.

ASLAN003 has also demonstrated “potent” inhibition of DHODH, according to ASLAN. In fact, the company said the binding affinity of ASLAN003 to DHODH has proven to be up to 2 orders of magnitude stronger than first-generation DHODH inhibitors such as leflunomide and teriflunomide.

ASLAN also said ASLAN003 should not confer the same toxicities as first-generation DHODH inhibitors and other novel AML therapies.

For example, leflunomide and teriflunomide, which may cause significant liver toxicity, take between 3 and 4 weeks to build to therapeutic levels and 2 years to be cleared completely after treatment is stopped.

ASLAN003, on the other hand, reaches full exposure in 24 hours and has a half-life of 18 hours.

Finally, ASLAN003 has been shown to differentiate blast cells into granulocytes in AML cell lines that do not respond to all-trans retinoic acid. These results were published in Cell in 2016.

Because of this research, ASLAN believes ASLAN003 may be effective in patients who do not respond to all-trans retinoic acid.

About 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.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to ASLAN003 as a treatment for acute myeloid leukemia (AML).

ASLAN003 is a small molecule inhibitor of the human dihydroorotate dehydrogenase (DHODH) enzyme.

This second-generation DHODH inhibitor is being developed by ASLAN Pharmaceuticals.

The company is currently conducting a phase 2 trial (NCT03451084) of ASLAN003 in patients with newly diagnosed or relapsed/refractory AML.

The goals of this trial are to determine the optimum dose of ASLAN003 as monotherapy and assess the drug’s efficacy by overall complete remission rate. ASLAN expects to report interim data from this trial in the second half of this year.

ASLAN has already completed a phase 1 trial (NCT01992367) of ASLAN003 in healthy volunteers.

Results suggested that ASLAN003 has an “excellent” pharmacokinetic profile, according to ASLAN, and the drug was considered well tolerated in the volunteers.

ASLAN003 has also demonstrated “potent” inhibition of DHODH, according to ASLAN. In fact, the company said the binding affinity of ASLAN003 to DHODH has proven to be up to 2 orders of magnitude stronger than first-generation DHODH inhibitors such as leflunomide and teriflunomide.

ASLAN also said ASLAN003 should not confer the same toxicities as first-generation DHODH inhibitors and other novel AML therapies.

For example, leflunomide and teriflunomide, which may cause significant liver toxicity, take between 3 and 4 weeks to build to therapeutic levels and 2 years to be cleared completely after treatment is stopped.

ASLAN003, on the other hand, reaches full exposure in 24 hours and has a half-life of 18 hours.

Finally, ASLAN003 has been shown to differentiate blast cells into granulocytes in AML cell lines that do not respond to all-trans retinoic acid. These results were published in Cell in 2016.

Because of this research, ASLAN believes ASLAN003 may be effective in patients who do not respond to all-trans retinoic acid.

About 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.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to ASLAN003 as a treatment for acute myeloid leukemia (AML).

ASLAN003 is a small molecule inhibitor of the human dihydroorotate dehydrogenase (DHODH) enzyme.

This second-generation DHODH inhibitor is being developed by ASLAN Pharmaceuticals.

The company is currently conducting a phase 2 trial (NCT03451084) of ASLAN003 in patients with newly diagnosed or relapsed/refractory AML.

The goals of this trial are to determine the optimum dose of ASLAN003 as monotherapy and assess the drug’s efficacy by overall complete remission rate. ASLAN expects to report interim data from this trial in the second half of this year.

ASLAN has already completed a phase 1 trial (NCT01992367) of ASLAN003 in healthy volunteers.

Results suggested that ASLAN003 has an “excellent” pharmacokinetic profile, according to ASLAN, and the drug was considered well tolerated in the volunteers.

ASLAN003 has also demonstrated “potent” inhibition of DHODH, according to ASLAN. In fact, the company said the binding affinity of ASLAN003 to DHODH has proven to be up to 2 orders of magnitude stronger than first-generation DHODH inhibitors such as leflunomide and teriflunomide.

ASLAN also said ASLAN003 should not confer the same toxicities as first-generation DHODH inhibitors and other novel AML therapies.

For example, leflunomide and teriflunomide, which may cause significant liver toxicity, take between 3 and 4 weeks to build to therapeutic levels and 2 years to be cleared completely after treatment is stopped.

ASLAN003, on the other hand, reaches full exposure in 24 hours and has a half-life of 18 hours.

Finally, ASLAN003 has been shown to differentiate blast cells into granulocytes in AML cell lines that do not respond to all-trans retinoic acid. These results were published in Cell in 2016.

Because of this research, ASLAN believes ASLAN003 may be effective in patients who do not respond to all-trans retinoic acid.

About 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.

The Food and Drug Administration has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.

In this trial (NCT02576301), researchers are evaluating OXi4503 alone and in combination with cytarabine in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The partial clinical hold applies to the 12.2 mg/m² dose of OXi4503. The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m². Additional data on patients receiving OXi4503 at 9.76 mg/m² must be evaluated before dosing at 12.2 mg/m² can be resumed.

The partial clinical hold is a result of two potential dose-limiting toxicities (DLTs) observed at the 12.2-mg/m² dose level: hypotension, which occurred shortly after initial treatment with OXi4503, and acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.

Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.

“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics Inc., the company developing OXi4503, said in a statement.

In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.

In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. OXi4503 demonstrated preliminary evidence of disease response in heavily pretreated, refractory AML and advanced MDS.

The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.

Results from this study were presented at the 2013 annual meeting of the American Society of Hematology.

In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.

The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS. It is also aimed at determining the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.

The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.

[email protected]

The Food and Drug Administration has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.

In this trial (NCT02576301), researchers are evaluating OXi4503 alone and in combination with cytarabine in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The partial clinical hold applies to the 12.2 mg/m² dose of OXi4503. The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m². Additional data on patients receiving OXi4503 at 9.76 mg/m² must be evaluated before dosing at 12.2 mg/m² can be resumed.

The partial clinical hold is a result of two potential dose-limiting toxicities (DLTs) observed at the 12.2-mg/m² dose level: hypotension, which occurred shortly after initial treatment with OXi4503, and acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.

Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.

“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics Inc., the company developing OXi4503, said in a statement.

In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.

In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. OXi4503 demonstrated preliminary evidence of disease response in heavily pretreated, refractory AML and advanced MDS.

The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.

Results from this study were presented at the 2013 annual meeting of the American Society of Hematology.

In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.

The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS. It is also aimed at determining the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.

The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.

[email protected]

The Food and Drug Administration has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.

In this trial (NCT02576301), researchers are evaluating OXi4503 alone and in combination with cytarabine in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The partial clinical hold applies to the 12.2 mg/m² dose of OXi4503. The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m². Additional data on patients receiving OXi4503 at 9.76 mg/m² must be evaluated before dosing at 12.2 mg/m² can be resumed.

The partial clinical hold is a result of two potential dose-limiting toxicities (DLTs) observed at the 12.2-mg/m² dose level: hypotension, which occurred shortly after initial treatment with OXi4503, and acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.

Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.

“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics Inc., the company developing OXi4503, said in a statement.

In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.

In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. OXi4503 demonstrated preliminary evidence of disease response in heavily pretreated, refractory AML and advanced MDS.

The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.

Results from this study were presented at the 2013 annual meeting of the American Society of Hematology.

In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.

The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS. It is also aimed at determining the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.

The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.

[email protected]

Photo by Rhoda Baer

New research suggests that better access to quality care may reduce disparities in survival between cancer patients living in rural areas of the US and those living in urban areas.

The study showed that urban and rural cancer patients had similar survival outcomes when they were enrolled in clinical trials.

These results, published in JAMA Network Open, cast new light on decades of research showing that cancer patients living in rural areas don’t live as long as urban cancer patients.

“These findings were a surprise, since we thought we might find the same disparities others had found,” said study author Joseph Unger, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“But clinical trials are a key difference here. In trials, patients are uniformly assessed, treated, and followed under a strict, guideline-driven protocol. This suggests that giving people with cancer access to uniform treatment strategies could help resolve the disparities in outcomes that we see between rural and urban patients.”

Dr Unger and his colleagues studied data on 36,995 patients who were enrolled in 44 phase 3 or phase 2/3 SWOG trials from 1986 through 2012. All 50 states were represented.

Patients had 17 different cancer types, including acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM).

Using US Department of Agriculture population classifications known as Rural-Urban Continuum Codes, the researchers categorized the patients as either rural or urban and analyzed their outcomes.

A minority of patients (19.4%, n=7184) were from rural locations. They were significantly more likely than urban patients to be 65 or older (P<0.001) and significantly less likely to be black (vs all other races; P<0.001).

However, there was no significant between-group difference in sex (P=0.53), and all major US geographic regions (West, Midwest, South, and Northeast) were represented.

Results

The researchers limited their analysis of survival to the first 5 years after trial enrollment to emphasize outcomes related to cancer and its treatment. They looked at overall survival (OS) as well as cancer-specific survival.

The team found no meaningful difference in OS or cancer-specific survival between rural and urban patients for 16 of the 17 cancer types.

The exception was estrogen receptor-negative, progesterone receptor-negative breast cancer. Rural patients with this cancer didn’t live as long as their urban counterparts. The hazard ratio (HR) was 1.27 (95% CI, 1.06-1.51; P=0.008) for OS and 1.26 (95% CI, 1.04-1.52; P=0.02) for cancer-specific survival.

The researchers believe this finding could be attributed to a few factors, including timely access to follow-up chemotherapy after patients’ first round of cancer treatment.

Although there were no significant survival differences for patients with hematologic malignancies, rural patients had slightly better OS if they had advanced indolent NHL or AML but slightly worse OS if they had MM or advanced aggressive NHL. The HRs were as follows:

• Advanced indolent NHL—HR=0.91 (95% CI, 0.64-1.29; P=0.60)
• AML—HR=0.94 (95% CI, 0.83-1.06; P=0.29)
• MM—HR=1.05 (95% CI, 0.93-1.18, P=0.46)
• Advanced aggressive NHL—HR=1.05 (95% CI, 0.87-1.27; P=0.60).

Rural patients had slightly better cancer-specific survival if they had advanced indolent NHL but slightly worse cancer-specific survival if they had AML, MM, or advanced aggressive NHL. The HRs were as follows:

• Advanced indolent NHL—HR=0.98 (95% CI, 0.66-1.45; P=0.90)
• AML—HR=1.01 (95% CI, 0.86-1.20; P=0.87)
• MM—HR=1.04 (95% CI, 0.90-1.20; P=0.60)
• Advanced aggressive NHL—HR=1.08 (95% CI, 0.87-1.34; P=0.50).

The researchers said these findings suggest it is access to care, and not other characteristics, that drive the survival disparities typically observed between urban and rural cancer patients.

“If people diagnosed with cancer, regardless of where they live, receive similar care and have similar outcomes, then a reasonable inference is that the best way to improve outcomes for rural patients is to improve their access to quality care,” Dr Unger said.

This research was supported by the National Cancer Institute and the HOPE Foundation. The researchers reported financial relationships with various pharmaceutical companies.

Photo by Rhoda Baer

New research suggests that better access to quality care may reduce disparities in survival between cancer patients living in rural areas of the US and those living in urban areas.

The study showed that urban and rural cancer patients had similar survival outcomes when they were enrolled in clinical trials.

These results, published in JAMA Network Open, cast new light on decades of research showing that cancer patients living in rural areas don’t live as long as urban cancer patients.

“These findings were a surprise, since we thought we might find the same disparities others had found,” said study author Joseph Unger, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“But clinical trials are a key difference here. In trials, patients are uniformly assessed, treated, and followed under a strict, guideline-driven protocol. This suggests that giving people with cancer access to uniform treatment strategies could help resolve the disparities in outcomes that we see between rural and urban patients.”

Dr Unger and his colleagues studied data on 36,995 patients who were enrolled in 44 phase 3 or phase 2/3 SWOG trials from 1986 through 2012. All 50 states were represented.

Patients had 17 different cancer types, including acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM).

Using US Department of Agriculture population classifications known as Rural-Urban Continuum Codes, the researchers categorized the patients as either rural or urban and analyzed their outcomes.

A minority of patients (19.4%, n=7184) were from rural locations. They were significantly more likely than urban patients to be 65 or older (P<0.001) and significantly less likely to be black (vs all other races; P<0.001).

However, there was no significant between-group difference in sex (P=0.53), and all major US geographic regions (West, Midwest, South, and Northeast) were represented.

Results

The researchers limited their analysis of survival to the first 5 years after trial enrollment to emphasize outcomes related to cancer and its treatment. They looked at overall survival (OS) as well as cancer-specific survival.

The team found no meaningful difference in OS or cancer-specific survival between rural and urban patients for 16 of the 17 cancer types.

The exception was estrogen receptor-negative, progesterone receptor-negative breast cancer. Rural patients with this cancer didn’t live as long as their urban counterparts. The hazard ratio (HR) was 1.27 (95% CI, 1.06-1.51; P=0.008) for OS and 1.26 (95% CI, 1.04-1.52; P=0.02) for cancer-specific survival.

The researchers believe this finding could be attributed to a few factors, including timely access to follow-up chemotherapy after patients’ first round of cancer treatment.

Although there were no significant survival differences for patients with hematologic malignancies, rural patients had slightly better OS if they had advanced indolent NHL or AML but slightly worse OS if they had MM or advanced aggressive NHL. The HRs were as follows:

• Advanced indolent NHL—HR=0.91 (95% CI, 0.64-1.29; P=0.60)
• AML—HR=0.94 (95% CI, 0.83-1.06; P=0.29)
• MM—HR=1.05 (95% CI, 0.93-1.18, P=0.46)
• Advanced aggressive NHL—HR=1.05 (95% CI, 0.87-1.27; P=0.60).

Rural patients had slightly better cancer-specific survival if they had advanced indolent NHL but slightly worse cancer-specific survival if they had AML, MM, or advanced aggressive NHL. The HRs were as follows:

• Advanced indolent NHL—HR=0.98 (95% CI, 0.66-1.45; P=0.90)
• AML—HR=1.01 (95% CI, 0.86-1.20; P=0.87)
• MM—HR=1.04 (95% CI, 0.90-1.20; P=0.60)
• Advanced aggressive NHL—HR=1.08 (95% CI, 0.87-1.34; P=0.50).

The researchers said these findings suggest it is access to care, and not other characteristics, that drive the survival disparities typically observed between urban and rural cancer patients.

“If people diagnosed with cancer, regardless of where they live, receive similar care and have similar outcomes, then a reasonable inference is that the best way to improve outcomes for rural patients is to improve their access to quality care,” Dr Unger said.

This research was supported by the National Cancer Institute and the HOPE Foundation. The researchers reported financial relationships with various pharmaceutical companies.

Photo by Rhoda Baer

New research suggests that better access to quality care may reduce disparities in survival between cancer patients living in rural areas of the US and those living in urban areas.

The study showed that urban and rural cancer patients had similar survival outcomes when they were enrolled in clinical trials.

These results, published in JAMA Network Open, cast new light on decades of research showing that cancer patients living in rural areas don’t live as long as urban cancer patients.

“These findings were a surprise, since we thought we might find the same disparities others had found,” said study author Joseph Unger, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“But clinical trials are a key difference here. In trials, patients are uniformly assessed, treated, and followed under a strict, guideline-driven protocol. This suggests that giving people with cancer access to uniform treatment strategies could help resolve the disparities in outcomes that we see between rural and urban patients.”

Dr Unger and his colleagues studied data on 36,995 patients who were enrolled in 44 phase 3 or phase 2/3 SWOG trials from 1986 through 2012. All 50 states were represented.

Patients had 17 different cancer types, including acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM).

Using US Department of Agriculture population classifications known as Rural-Urban Continuum Codes, the researchers categorized the patients as either rural or urban and analyzed their outcomes.

A minority of patients (19.4%, n=7184) were from rural locations. They were significantly more likely than urban patients to be 65 or older (P<0.001) and significantly less likely to be black (vs all other races; P<0.001).

However, there was no significant between-group difference in sex (P=0.53), and all major US geographic regions (West, Midwest, South, and Northeast) were represented.

Results

The researchers limited their analysis of survival to the first 5 years after trial enrollment to emphasize outcomes related to cancer and its treatment. They looked at overall survival (OS) as well as cancer-specific survival.

The team found no meaningful difference in OS or cancer-specific survival between rural and urban patients for 16 of the 17 cancer types.

The exception was estrogen receptor-negative, progesterone receptor-negative breast cancer. Rural patients with this cancer didn’t live as long as their urban counterparts. The hazard ratio (HR) was 1.27 (95% CI, 1.06-1.51; P=0.008) for OS and 1.26 (95% CI, 1.04-1.52; P=0.02) for cancer-specific survival.

The researchers believe this finding could be attributed to a few factors, including timely access to follow-up chemotherapy after patients’ first round of cancer treatment.

Although there were no significant survival differences for patients with hematologic malignancies, rural patients had slightly better OS if they had advanced indolent NHL or AML but slightly worse OS if they had MM or advanced aggressive NHL. The HRs were as follows:

• Advanced indolent NHL—HR=0.91 (95% CI, 0.64-1.29; P=0.60)
• AML—HR=0.94 (95% CI, 0.83-1.06; P=0.29)
• MM—HR=1.05 (95% CI, 0.93-1.18, P=0.46)
• Advanced aggressive NHL—HR=1.05 (95% CI, 0.87-1.27; P=0.60).

Rural patients had slightly better cancer-specific survival if they had advanced indolent NHL but slightly worse cancer-specific survival if they had AML, MM, or advanced aggressive NHL. The HRs were as follows:

• Advanced indolent NHL—HR=0.98 (95% CI, 0.66-1.45; P=0.90)
• AML—HR=1.01 (95% CI, 0.86-1.20; P=0.87)
• MM—HR=1.04 (95% CI, 0.90-1.20; P=0.60)
• Advanced aggressive NHL—HR=1.08 (95% CI, 0.87-1.34; P=0.50).

The researchers said these findings suggest it is access to care, and not other characteristics, that drive the survival disparities typically observed between urban and rural cancer patients.

“If people diagnosed with cancer, regardless of where they live, receive similar care and have similar outcomes, then a reasonable inference is that the best way to improve outcomes for rural patients is to improve their access to quality care,” Dr Unger said.

This research was supported by the National Cancer Institute and the HOPE Foundation. The researchers reported financial relationships with various pharmaceutical companies.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.

In this trial (NCT02576301), researchers are evaluating OXi4503, alone and in combination with cytarabine, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The partial clinical hold applies to the 12.2 mg/m² dose of OXi4503.

The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m².

The agency said additional data on patients receiving OXi4503 at 9.76 mg/m² must be evaluated before dosing at 12.2 mg/m² can be resumed.

The partial clinical hold is a result of 2 potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m² dose level.

One DLT was hypotension, which occurred shortly after initial treatment with OXi4503. The other DLT was acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.

Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.

The study protocol generally defines a DLT as any grade 3 serious adverse event where a relationship to OXi4503 cannot be ruled out.

“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” said William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics, Inc., the company developing OXi4503.

About OXi4503

According to Mateon Therapeutics, OXi4503 has a dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules.

This alters the endothelial cell shape, releasing quiescent adherent tumor cells from bone marrow endothelial cells and activating the cell cycle, which makes the tumor cells vulnerable to chemotherapy.

OXi4503 also kills tumor cells directly via myeloperoxidase activation of an orthoquinone cytotoxic mediator.

In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.

Clinical trials

In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. The goals were to determine the safety profile, maximum tolerated dose, and biologic activity of OXi4503.

The researchers said OXi4503 demonstrated preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS.

The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.

Results from this study were presented at the 2013 ASH Annual Meeting.

In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.

The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS.

The phase 1 portion was also intended to determine the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.

The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.

In this trial (NCT02576301), researchers are evaluating OXi4503, alone and in combination with cytarabine, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The partial clinical hold applies to the 12.2 mg/m² dose of OXi4503.

The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m².

The agency said additional data on patients receiving OXi4503 at 9.76 mg/m² must be evaluated before dosing at 12.2 mg/m² can be resumed.

The partial clinical hold is a result of 2 potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m² dose level.

One DLT was hypotension, which occurred shortly after initial treatment with OXi4503. The other DLT was acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.

Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.

The study protocol generally defines a DLT as any grade 3 serious adverse event where a relationship to OXi4503 cannot be ruled out.

“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” said William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics, Inc., the company developing OXi4503.

About OXi4503

According to Mateon Therapeutics, OXi4503 has a dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules.

This alters the endothelial cell shape, releasing quiescent adherent tumor cells from bone marrow endothelial cells and activating the cell cycle, which makes the tumor cells vulnerable to chemotherapy.

OXi4503 also kills tumor cells directly via myeloperoxidase activation of an orthoquinone cytotoxic mediator.

In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.

Clinical trials

In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. The goals were to determine the safety profile, maximum tolerated dose, and biologic activity of OXi4503.

The researchers said OXi4503 demonstrated preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS.

The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.

Results from this study were presented at the 2013 ASH Annual Meeting.

In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.

The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS.

The phase 1 portion was also intended to determine the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.

The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has placed a partial clinical hold on a phase 1b/2 study of OXi4503, a vascular disrupting agent.

In this trial (NCT02576301), researchers are evaluating OXi4503, alone and in combination with cytarabine, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The partial clinical hold applies to the 12.2 mg/m² dose of OXi4503.

The FDA is allowing the continued treatment and enrollment of patients using a dose of 9.76 mg/m².

The agency said additional data on patients receiving OXi4503 at 9.76 mg/m² must be evaluated before dosing at 12.2 mg/m² can be resumed.

The partial clinical hold is a result of 2 potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m² dose level.

One DLT was hypotension, which occurred shortly after initial treatment with OXi4503. The other DLT was acute hypoxic respiratory failure, which occurred approximately 2 weeks after receiving OXi4503 and cytarabine.

Both events were deemed “possibly related” to OXi4503, and both patients recovered following treatment.

The study protocol generally defines a DLT as any grade 3 serious adverse event where a relationship to OXi4503 cannot be ruled out.

“Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed 2 complete remissions in the 4 patients that we treated,” said William D. Schwieterman, MD, chief executive officer of Mateon Therapeutics, Inc., the company developing OXi4503.

About OXi4503

According to Mateon Therapeutics, OXi4503 has a dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules.

This alters the endothelial cell shape, releasing quiescent adherent tumor cells from bone marrow endothelial cells and activating the cell cycle, which makes the tumor cells vulnerable to chemotherapy.

OXi4503 also kills tumor cells directly via myeloperoxidase activation of an orthoquinone cytotoxic mediator.

In preclinical research, OXi4503 demonstrated activity against AML, both when given alone and in combination with bevacizumab. These results were published in Blood in 2010.

Clinical trials

In a phase 1 trial (NCT01085656), researchers evaluated OXi4503 in patients with relapsed or refractory AML or MDS. The goals were to determine the safety profile, maximum tolerated dose, and biologic activity of OXi4503.

The researchers said OXi4503 demonstrated preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS.

The maximum tolerated dose of OXi4503 was not identified, but adverse events attributable to the drug included hypertension, bone pain, fever, anemia, thrombocytopenia, and coagulopathies.

Results from this study were presented at the 2013 ASH Annual Meeting.

In 2015, Mateon Therapeutics initiated the phase 1b/2 study of OXi4503 (NCT02576301) that is now on partial clinical hold.

The phase 1 portion of this study was designed to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of single-agent OXi4503 in patients with relapsed/refractory AML and MDS.

The phase 1 portion was also intended to determine the safety, pharmacokinetics, and pharmacodynamics of OXi4503 plus intermediate-dose cytarabine.

The goal of the phase 2 portion is to assess the preliminary efficacy of OXi4503 and cytarabine in patients with AML and MDS.

Photo by Bill Branson

The US Food and Drug Administration(FDA) has accepted for priority review the biologics license application seeking approval for tagraxofusp (Elzonris, SL-401) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN).

The FDA expects to make a decision on this application by February 21, 2019.

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

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

About tagraxofusp

Tagraxofusp is a targeted therapy directed to CD123, a cell surface receptor expressed on a range of malignancies. The drug is being developed by Stemline Therapeutics, Inc.

In addition to priority review, tagraxofusp has breakthrough therapy designation and orphan drug designation from the FDA.

Tagraxofusp has produced favorable early results in a phase 2 trial of patients with BPDCN. Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) in June.

Results were presented for 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN.

Three patients received tagraxofusp at 7 μg/kg/day on days 1 to 5 of a 21-day cycle, and the rest received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle.

Among patients who received the 12 μg/kg/day dose, the overall response rate was 83% (35/42). The overall response rate was 90% (26/29) in the previously untreated patients and 69% (9/13) in relapsed/refractory patients.

The composite complete response rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival had not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Safety results were presented for 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with diseases other than BPDCN, although adverse events (AEs) were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

Another common AE was capillary leak syndrome (CLS), which occurred in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Researchers found they could manage the CLS with monitoring and protocol adjustments.

Photo by Bill Branson

The US Food and Drug Administration(FDA) has accepted for priority review the biologics license application seeking approval for tagraxofusp (Elzonris, SL-401) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN).

The FDA expects to make a decision on this application by February 21, 2019.

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

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

About tagraxofusp

Tagraxofusp is a targeted therapy directed to CD123, a cell surface receptor expressed on a range of malignancies. The drug is being developed by Stemline Therapeutics, Inc.

In addition to priority review, tagraxofusp has breakthrough therapy designation and orphan drug designation from the FDA.

Tagraxofusp has produced favorable early results in a phase 2 trial of patients with BPDCN. Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) in June.

Results were presented for 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN.

Three patients received tagraxofusp at 7 μg/kg/day on days 1 to 5 of a 21-day cycle, and the rest received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle.

Among patients who received the 12 μg/kg/day dose, the overall response rate was 83% (35/42). The overall response rate was 90% (26/29) in the previously untreated patients and 69% (9/13) in relapsed/refractory patients.

The composite complete response rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival had not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Safety results were presented for 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with diseases other than BPDCN, although adverse events (AEs) were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

Another common AE was capillary leak syndrome (CLS), which occurred in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Researchers found they could manage the CLS with monitoring and protocol adjustments.

Photo by Bill Branson

The US Food and Drug Administration(FDA) has accepted for priority review the biologics license application seeking approval for tagraxofusp (Elzonris, SL-401) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN).

The FDA expects to make a decision on this application by February 21, 2019.

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

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

About tagraxofusp

Tagraxofusp is a targeted therapy directed to CD123, a cell surface receptor expressed on a range of malignancies. The drug is being developed by Stemline Therapeutics, Inc.

In addition to priority review, tagraxofusp has breakthrough therapy designation and orphan drug designation from the FDA.

Tagraxofusp has produced favorable early results in a phase 2 trial of patients with BPDCN. Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) in June.

Results were presented for 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN.

Three patients received tagraxofusp at 7 μg/kg/day on days 1 to 5 of a 21-day cycle, and the rest received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle.

Among patients who received the 12 μg/kg/day dose, the overall response rate was 83% (35/42). The overall response rate was 90% (26/29) in the previously untreated patients and 69% (9/13) in relapsed/refractory patients.

The composite complete response rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival had not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Safety results were presented for 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with diseases other than BPDCN, although adverse events (AEs) were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

Another common AE was capillary leak syndrome (CLS), which occurred in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Researchers found they could manage the CLS with monitoring and protocol adjustments.

Photo by Luis Alvaz

Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.

The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.

The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.

Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.

The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.

With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant.

More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:

• Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
• NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
• NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
• NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).

Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.

However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.

“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”

The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies. 

Photo by Luis Alvaz

Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.

The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.

The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.

Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.

The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.

With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant.

More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:

• Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
• NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
• NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
• NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).

Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.

However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.

“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”

The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies. 

Photo by Luis Alvaz

Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.

The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.

The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.

Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.

The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.

With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant.

More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:

• Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
• NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
• NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
• NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).

Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.

However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.

“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”

The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies. 

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Patients undergoing autologous hematopoietic cell transplantation for lymphoma or plasma cell myeloma have 10-100 times the risk of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) seen in the general population, according to a retrospective cohort study.

The elevated risk also exceeds that of similar patients largely untreated with autotransplant.

Exposure to DNA-damaging drugs and ionizing radiation – both used in autotransplant – is known to increase risk of these treatment-related myeloid neoplasms, according to Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation and his colleagues. Concern about this complication has been growing as long-term survivorship after transplant improves.

The investigators analyzed data reported to the Center for International Blood and Marrow Transplant Research. Analyses were based on 9,028 patients undergoing autotransplant during 1995-2010 for Hodgkin lymphoma (916 patients), non-Hodgkin lymphoma (3,546 patients), or plasma cell myeloma (4,566 patients). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant. More aggressive transplantation protocols increased the likelihood of this outcome: Risk was higher for patients with Hodgkin lymphoma who received conditioning with total body radiation versus chemotherapy alone (hazard ratio, 4.0); patients with non-Hodgkin lymphoma who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen; patients with non-Hodgkin lymphoma or plasma cell myeloma who received three or more lines of chemotherapy versus just one line (HR, 1.9 and 1.8, respectively); and patients with non-Hodgkin lymphoma who underwent transplantation in 2005-2010 versus 1995-1999 (HR, 2.1).

Patients reported to Surveillance, Epidemiology and End Results (SEER) database with the same lymphoma and plasma cell myeloma diagnoses, few of whom underwent autotransplant, had risks of AML and MDS that were 5-10 times higher than the background level in the population. But the study autotransplant cohort had a risk of AML that was 10-50 times higher, and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for the autotransplant, but this hypothesis can only be tested in a prospective study,” Dr. Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown. “One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased posttransplant surveillance resulted in a deficiency of AML,” they wrote. “A second is based on steeper MDS versus AML incidences versus age … and the possibility that transplantation recipient marrow ages (i.e., marrow biological ages) are perhaps decades older than calendar ages.”

The Center for International Blood and Marrow Transplant Research is supported by several U.S. government agencies and numerous pharmaceutical companies. The authors reported that they had no relevant conflicts of interest.

SOURCE: Radivoyevitch T et al. Leuk Res. 2018 Jul 19. pii: S0145-2126(18)30160-7.

Patients undergoing autologous hematopoietic cell transplantation for lymphoma or plasma cell myeloma have 10-100 times the risk of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) seen in the general population, according to a retrospective cohort study.

The elevated risk also exceeds that of similar patients largely untreated with autotransplant.

Exposure to DNA-damaging drugs and ionizing radiation – both used in autotransplant – is known to increase risk of these treatment-related myeloid neoplasms, according to Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation and his colleagues. Concern about this complication has been growing as long-term survivorship after transplant improves.

The investigators analyzed data reported to the Center for International Blood and Marrow Transplant Research. Analyses were based on 9,028 patients undergoing autotransplant during 1995-2010 for Hodgkin lymphoma (916 patients), non-Hodgkin lymphoma (3,546 patients), or plasma cell myeloma (4,566 patients). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant. More aggressive transplantation protocols increased the likelihood of this outcome: Risk was higher for patients with Hodgkin lymphoma who received conditioning with total body radiation versus chemotherapy alone (hazard ratio, 4.0); patients with non-Hodgkin lymphoma who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen; patients with non-Hodgkin lymphoma or plasma cell myeloma who received three or more lines of chemotherapy versus just one line (HR, 1.9 and 1.8, respectively); and patients with non-Hodgkin lymphoma who underwent transplantation in 2005-2010 versus 1995-1999 (HR, 2.1).

Patients reported to Surveillance, Epidemiology and End Results (SEER) database with the same lymphoma and plasma cell myeloma diagnoses, few of whom underwent autotransplant, had risks of AML and MDS that were 5-10 times higher than the background level in the population. But the study autotransplant cohort had a risk of AML that was 10-50 times higher, and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for the autotransplant, but this hypothesis can only be tested in a prospective study,” Dr. Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown. “One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased posttransplant surveillance resulted in a deficiency of AML,” they wrote. “A second is based on steeper MDS versus AML incidences versus age … and the possibility that transplantation recipient marrow ages (i.e., marrow biological ages) are perhaps decades older than calendar ages.”

The Center for International Blood and Marrow Transplant Research is supported by several U.S. government agencies and numerous pharmaceutical companies. The authors reported that they had no relevant conflicts of interest.

SOURCE: Radivoyevitch T et al. Leuk Res. 2018 Jul 19. pii: S0145-2126(18)30160-7.

Patients undergoing autologous hematopoietic cell transplantation for lymphoma or plasma cell myeloma have 10-100 times the risk of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) seen in the general population, according to a retrospective cohort study.

The elevated risk also exceeds that of similar patients largely untreated with autotransplant.

Exposure to DNA-damaging drugs and ionizing radiation – both used in autotransplant – is known to increase risk of these treatment-related myeloid neoplasms, according to Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation and his colleagues. Concern about this complication has been growing as long-term survivorship after transplant improves.

The investigators analyzed data reported to the Center for International Blood and Marrow Transplant Research. Analyses were based on 9,028 patients undergoing autotransplant during 1995-2010 for Hodgkin lymphoma (916 patients), non-Hodgkin lymphoma (3,546 patients), or plasma cell myeloma (4,566 patients). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant. More aggressive transplantation protocols increased the likelihood of this outcome: Risk was higher for patients with Hodgkin lymphoma who received conditioning with total body radiation versus chemotherapy alone (hazard ratio, 4.0); patients with non-Hodgkin lymphoma who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen; patients with non-Hodgkin lymphoma or plasma cell myeloma who received three or more lines of chemotherapy versus just one line (HR, 1.9 and 1.8, respectively); and patients with non-Hodgkin lymphoma who underwent transplantation in 2005-2010 versus 1995-1999 (HR, 2.1).

Patients reported to Surveillance, Epidemiology and End Results (SEER) database with the same lymphoma and plasma cell myeloma diagnoses, few of whom underwent autotransplant, had risks of AML and MDS that were 5-10 times higher than the background level in the population. But the study autotransplant cohort had a risk of AML that was 10-50 times higher, and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for the autotransplant, but this hypothesis can only be tested in a prospective study,” Dr. Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown. “One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased posttransplant surveillance resulted in a deficiency of AML,” they wrote. “A second is based on steeper MDS versus AML incidences versus age … and the possibility that transplantation recipient marrow ages (i.e., marrow biological ages) are perhaps decades older than calendar ages.”

The Center for International Blood and Marrow Transplant Research is supported by several U.S. government agencies and numerous pharmaceutical companies. The authors reported that they had no relevant conflicts of interest.

SOURCE: Radivoyevitch T et al. Leuk Res. 2018 Jul 19. pii: S0145-2126(18)30160-7.