Myelodysplastic Syndrome

Photo by Petr Kratochvil

An analysis of more than 2,000 U.S. patients with blood cancers revealed an average healthcare cost of almost $157,000 in the first year after diagnosis.

Costs were highest for acute leukemia patients—almost triple the average for all blood cancers.

Out-of-pocket (OOP) costs were initially highest for acute leukemia patients. However, over time, OOP costs became highest for patients with multiple myeloma.

These results are included in a report commissioned by the Leukemia & Lymphoma Society and prepared by the actuarial firm Milliman.

The report is based on data from the Truven Health MarketScan commercial claims databases.

The cost figures are drawn from data for 2,332 patients, ages 18 to 64, who were diagnosed with blood cancer in 2014 and followed through 2016. This includes the following:

• 1,468 patients with lymphoma
• 286 with chronic leukemia
• 282 with multiple myeloma
• 148 with acute leukemia
• 148 with bone marrow disorders (myelodysplastic syndromes).

The average allowed spending—the amount paid by the payer and patient combined—in the first 12 months after diagnosis was:

• $156,845 overall
• $463,414 for acute leukemia
• $213,879 for multiple myeloma
• $133,744 for bone marrow disorders
• $130,545 for lymphoma
• $88,913 for chronic leukemia.

Differences in OOP costs were smaller, although OOP spending was 32% higher for acute leukemia patients than the overall average.

Average OOP costs—which include coinsurance, copay, and deductible—in the first 12 months after diagnosis were:

• $3,877 overall
• $5,147 for acute leukemia
• $4,849 for multiple myeloma
• $3,695 for lymphoma
• $3,480 for chronic leukemia
• $3,336 for bone marrow disorders.

Although OOP costs were initially highest for acute leukemia patients, over time, costs for multiple myeloma patients became the highest.

The average OOP costs in the month of diagnosis were $1,637 for acute leukemia patients and $1,210 for multiple myeloma patients.

The total accumulated OOP costs 3 years after diagnosis were $8,797 for acute leukemia and $9,127 for multiple myeloma. For the other blood cancers, the average 3-year accumulated OOP costs were under $7,800.

The Leukemia & Lymphoma Society received support from Pfizer, Genentech, and Amgen for this work.

Photo by Petr Kratochvil

An analysis of more than 2,000 U.S. patients with blood cancers revealed an average healthcare cost of almost $157,000 in the first year after diagnosis.

Costs were highest for acute leukemia patients—almost triple the average for all blood cancers.

Out-of-pocket (OOP) costs were initially highest for acute leukemia patients. However, over time, OOP costs became highest for patients with multiple myeloma.

These results are included in a report commissioned by the Leukemia & Lymphoma Society and prepared by the actuarial firm Milliman.

The report is based on data from the Truven Health MarketScan commercial claims databases.

The cost figures are drawn from data for 2,332 patients, ages 18 to 64, who were diagnosed with blood cancer in 2014 and followed through 2016. This includes the following:

• 1,468 patients with lymphoma
• 286 with chronic leukemia
• 282 with multiple myeloma
• 148 with acute leukemia
• 148 with bone marrow disorders (myelodysplastic syndromes).

The average allowed spending—the amount paid by the payer and patient combined—in the first 12 months after diagnosis was:

• $156,845 overall
• $463,414 for acute leukemia
• $213,879 for multiple myeloma
• $133,744 for bone marrow disorders
• $130,545 for lymphoma
• $88,913 for chronic leukemia.

Differences in OOP costs were smaller, although OOP spending was 32% higher for acute leukemia patients than the overall average.

Average OOP costs—which include coinsurance, copay, and deductible—in the first 12 months after diagnosis were:

• $3,877 overall
• $5,147 for acute leukemia
• $4,849 for multiple myeloma
• $3,695 for lymphoma
• $3,480 for chronic leukemia
• $3,336 for bone marrow disorders.

Although OOP costs were initially highest for acute leukemia patients, over time, costs for multiple myeloma patients became the highest.

The average OOP costs in the month of diagnosis were $1,637 for acute leukemia patients and $1,210 for multiple myeloma patients.

The total accumulated OOP costs 3 years after diagnosis were $8,797 for acute leukemia and $9,127 for multiple myeloma. For the other blood cancers, the average 3-year accumulated OOP costs were under $7,800.

The Leukemia & Lymphoma Society received support from Pfizer, Genentech, and Amgen for this work.

Photo by Petr Kratochvil

An analysis of more than 2,000 U.S. patients with blood cancers revealed an average healthcare cost of almost $157,000 in the first year after diagnosis.

Costs were highest for acute leukemia patients—almost triple the average for all blood cancers.

Out-of-pocket (OOP) costs were initially highest for acute leukemia patients. However, over time, OOP costs became highest for patients with multiple myeloma.

These results are included in a report commissioned by the Leukemia & Lymphoma Society and prepared by the actuarial firm Milliman.

The report is based on data from the Truven Health MarketScan commercial claims databases.

The cost figures are drawn from data for 2,332 patients, ages 18 to 64, who were diagnosed with blood cancer in 2014 and followed through 2016. This includes the following:

• 1,468 patients with lymphoma
• 286 with chronic leukemia
• 282 with multiple myeloma
• 148 with acute leukemia
• 148 with bone marrow disorders (myelodysplastic syndromes).

The average allowed spending—the amount paid by the payer and patient combined—in the first 12 months after diagnosis was:

• $156,845 overall
• $463,414 for acute leukemia
• $213,879 for multiple myeloma
• $133,744 for bone marrow disorders
• $130,545 for lymphoma
• $88,913 for chronic leukemia.

Differences in OOP costs were smaller, although OOP spending was 32% higher for acute leukemia patients than the overall average.

Average OOP costs—which include coinsurance, copay, and deductible—in the first 12 months after diagnosis were:

• $3,877 overall
• $5,147 for acute leukemia
• $4,849 for multiple myeloma
• $3,695 for lymphoma
• $3,480 for chronic leukemia
• $3,336 for bone marrow disorders.

Although OOP costs were initially highest for acute leukemia patients, over time, costs for multiple myeloma patients became the highest.

The average OOP costs in the month of diagnosis were $1,637 for acute leukemia patients and $1,210 for multiple myeloma patients.

The total accumulated OOP costs 3 years after diagnosis were $8,797 for acute leukemia and $9,127 for multiple myeloma. For the other blood cancers, the average 3-year accumulated OOP costs were under $7,800.

The Leukemia & Lymphoma Society received support from Pfizer, Genentech, and Amgen for this work.

Photo courtesy of GSK

Results from the phase 3 SUPPORT trial suggest there is no role for the combination of eltrombopag and azacitidine in patients with intermediate- or high-risk myelodysplastic syndromes (MDS), according to investigators.

Adding eltrombopag to azacitidine worsened platelet recovery, reduced the overall response rate, and did not improve overall or progression-free survival when compared to azacitidine plus placebo.

Investigators had hypothesized that eltrombopag would reduce the thrombocytopenia exacerbated by azacitidine treatment.

Not only was this not the case, but the investigators observed a trend toward increased progression to acute myeloid leukemia (AML) in eltrombopag-treated patients.

An independent monitoring committee recommended the trial be terminated early.

Michael Dickinson, MBBS, of Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia, and his colleagues reported results from the trial in Blood.

The investigators conducted the SUPPORT study (NCT02158936) to investigate the efficacy and safety of eltrombopag as platelet supportive care in patients with intermediate- to high-risk MDS and thrombocytopenia who were receiving azacitidine.

Study design

Investigators randomized patients 1:1 to eltrombopag or placebo in combination with azacitidine. Patients had to have at least one platelet count less than 75 x 10⁹/L within 28 days prior to the first azacitidine dose.

Patients received azacitidine subcutaneously at a dose of 75 mg/m² once daily on 7 consecutive days for 28 days.

Patients received eltrombopag or placebo at a starting dose of 200 mg/day (100 mg/day for East Asians), adjusted by 100 mg increments (50 mg increments for East Asians) to a maximum of 300 mg/day (150 mg/day for East Asians).

Patient disposition

Investigators enrolled 356 patients from 30 countries between June 2014 and December 2015, randomizing 179 patients to eltrombopag and 177 to placebo.

Patients were a median age of 70, 66% were male, 83% were white, and 47% had platelet counts between 20 and 50 x 10⁹/L.

At the start of the trial, 19% of patients (n=66) were platelet transfusion-dependent—16% (29/179) in the eltrombopag group and 21% (37/177) in the placebo group.

Treatment exposure

Patients received eltrombopag for a median of 83 days (range, 60 to 148) and placebo for a median of 149 days (range, 8 to 503).

For non-East Asian patients, the mean dose of eltrombopag was 205 mg/day (range, 65 to 293), and the mean dose of placebo was 245 mg/day (range, 107 to 316).

Sixty-eight patients (38%) in the eltrombopag arm received the recommended number of six or more azacitidine cycles, compared to 91 (51%) in the placebo arm.

Two patients in the eltrombopag arm did not receive treatment. Therefore, the safety analyses were conducted on the 177 treated patients in each arm.

Safety

The most common reason for treatment discontinuation was termination of the study. Thirty-two percent of patients in the eltrombopag cohort and 44% in the placebo cohort discontinued for this reason.

Patients had to discontinue eltrombopag or placebo if azacitidine was discontinued, and this occurred in 30% of patients in the eltrombopag group and 26% in the placebo group.

Twenty-two percent of eltrombopag-treated patients discontinued due to adverse events (AEs), compared with 14% in the placebo group.

The most common reasons for azacitidine discontinuation in the eltrombopag and placebo arms, respectively, were study termination (35% and 46%), AEs (25% and 19%), disease progression (15% and 14%), and patient decision (11% and 9%).

AEs with the greatest difference between the eltrombopag and placebo arms, respectively, were febrile neutropenia (31% and 21%), neutropenia (31% and 26%), nausea (31% and 26%), and diarrhea (25% and 14%).

Sixty-three of the 177 AEs in the eltrombopag group were suspected to be treatment-related, compared to 42 of 173 AEs in the placebo group.

One hundred twenty-eight (72%) serious AEs occurred in the eltrombopag arm, compared to 100 (56%) in the placebo arm.

Fifteen percent of the serious AEs were suspected to be related to eltrombopag treatment, compared to 4% of the serious AEs in the placebo group.

At the final analysis, 108 patients had died—57 (32%) in the eltrombopag group and 51 (29%) in the placebo group (hazard ratio [HR] 1.42; 95% CI 0.97, 2.08; nominal P=0.164).

The main causes of death were disease progression (28 in the eltrombopag group and 21 in the placebo group) and sepsis (18 in the eltrombopag group and 13 in the placebo group).

Efficacy

The study’s primary endpoint was the proportion of patients free of platelet transfusions during cycles one to four of azacitidine therapy.

At the final analysis, there were fewer patients in the eltrombopag arm than in the placebo arm who had achieved platelet transfusion independence—16% (28/179) and 31% (55/177), respectively. The odds ratio (OR) was 0.37 (95% CI 0.21, 0.65; two-sided P value=0.001).

Secondary efficacy endpoints included overall survival, disease response, duration of response, progression to AML, progression-free survival, and hematologic improvement.

The investigators pointed out that no formal statistical tests were performed for the secondary endpoints. Therefore, “statistical interpretation should be made with caution,” they wrote.

Overall response by IWG criteria occurred in 20% of patients in the eltrombopag group and 35% of those in the placebo group, according to investigator assessment (OR=0.51; 95% CI 0.30, 0.86; nominal P=0.005).

There was no significant difference in hematologic improvement, overall survival, or progression-free survival between the treatment arms.

The investigators found a higher rate of progression to AML in the eltrombopag arm than in the placebo arm—15% and 9%, respectively (OR=1.59; 95% CI 0.81, 3.14; nominal P=0.079).

They pointed out that these results contrasted with those of recent clinical studies of eltrombopag monotherapy^1,2,3,4 in patients with MDS.

“[T]he findings of this trial were unexpected,” the investigators wrote.

They hypothesized that eltrombopag inhibits the effects of azacitidine when the drugs are given concomitantly. The issue is being studied further with ongoing research, they said.

The authors acknowledged financial support for medical editorial assistance provided by Novartis Pharmaceuticals Corporation.

Dr. Dickinson disclosed relationships with Celgene, Novartis, Janssen, Pfizer, and Roche. Senior study author Uwe Platzbecker, MD, disclosed relationships with Amgen, Celgene, GlaxoSmithKline, and Novartis.

1. Platzbecker U, et al Lancet Haematol. 2015;2(10):e417-e426. DOI: https://doi.org/10.1016/S2352-3026(15)00149-0

2. Oliva EN, et al. Lancet Haematol. 2017;4(3):e127-e136. DOI: https://doi.org/10.1016/S2352-3026(17)30012-1

3. Mittelman M, et al. Lancet Haematol. 2017;5(1):e34-e43. DOI: https://doi.org/10.1016/S2352-3026(17)30228-4

4. Buckstein R. Lancet Haematol. 2015;2(10):e396-e397. DOI: https://doi.org/10.1016/S2352-3026(15)00200-8

Photo courtesy of GSK

Results from the phase 3 SUPPORT trial suggest there is no role for the combination of eltrombopag and azacitidine in patients with intermediate- or high-risk myelodysplastic syndromes (MDS), according to investigators.

Adding eltrombopag to azacitidine worsened platelet recovery, reduced the overall response rate, and did not improve overall or progression-free survival when compared to azacitidine plus placebo.

Investigators had hypothesized that eltrombopag would reduce the thrombocytopenia exacerbated by azacitidine treatment.

Not only was this not the case, but the investigators observed a trend toward increased progression to acute myeloid leukemia (AML) in eltrombopag-treated patients.

An independent monitoring committee recommended the trial be terminated early.

Michael Dickinson, MBBS, of Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia, and his colleagues reported results from the trial in Blood.

The investigators conducted the SUPPORT study (NCT02158936) to investigate the efficacy and safety of eltrombopag as platelet supportive care in patients with intermediate- to high-risk MDS and thrombocytopenia who were receiving azacitidine.

Study design

Investigators randomized patients 1:1 to eltrombopag or placebo in combination with azacitidine. Patients had to have at least one platelet count less than 75 x 10⁹/L within 28 days prior to the first azacitidine dose.

Patients received azacitidine subcutaneously at a dose of 75 mg/m² once daily on 7 consecutive days for 28 days.

Patients received eltrombopag or placebo at a starting dose of 200 mg/day (100 mg/day for East Asians), adjusted by 100 mg increments (50 mg increments for East Asians) to a maximum of 300 mg/day (150 mg/day for East Asians).

Patient disposition

Investigators enrolled 356 patients from 30 countries between June 2014 and December 2015, randomizing 179 patients to eltrombopag and 177 to placebo.

Patients were a median age of 70, 66% were male, 83% were white, and 47% had platelet counts between 20 and 50 x 10⁹/L.

At the start of the trial, 19% of patients (n=66) were platelet transfusion-dependent—16% (29/179) in the eltrombopag group and 21% (37/177) in the placebo group.

Treatment exposure

Patients received eltrombopag for a median of 83 days (range, 60 to 148) and placebo for a median of 149 days (range, 8 to 503).

For non-East Asian patients, the mean dose of eltrombopag was 205 mg/day (range, 65 to 293), and the mean dose of placebo was 245 mg/day (range, 107 to 316).

Sixty-eight patients (38%) in the eltrombopag arm received the recommended number of six or more azacitidine cycles, compared to 91 (51%) in the placebo arm.

Two patients in the eltrombopag arm did not receive treatment. Therefore, the safety analyses were conducted on the 177 treated patients in each arm.

Safety

The most common reason for treatment discontinuation was termination of the study. Thirty-two percent of patients in the eltrombopag cohort and 44% in the placebo cohort discontinued for this reason.

Patients had to discontinue eltrombopag or placebo if azacitidine was discontinued, and this occurred in 30% of patients in the eltrombopag group and 26% in the placebo group.

Twenty-two percent of eltrombopag-treated patients discontinued due to adverse events (AEs), compared with 14% in the placebo group.

The most common reasons for azacitidine discontinuation in the eltrombopag and placebo arms, respectively, were study termination (35% and 46%), AEs (25% and 19%), disease progression (15% and 14%), and patient decision (11% and 9%).

AEs with the greatest difference between the eltrombopag and placebo arms, respectively, were febrile neutropenia (31% and 21%), neutropenia (31% and 26%), nausea (31% and 26%), and diarrhea (25% and 14%).

Sixty-three of the 177 AEs in the eltrombopag group were suspected to be treatment-related, compared to 42 of 173 AEs in the placebo group.

One hundred twenty-eight (72%) serious AEs occurred in the eltrombopag arm, compared to 100 (56%) in the placebo arm.

Fifteen percent of the serious AEs were suspected to be related to eltrombopag treatment, compared to 4% of the serious AEs in the placebo group.

At the final analysis, 108 patients had died—57 (32%) in the eltrombopag group and 51 (29%) in the placebo group (hazard ratio [HR] 1.42; 95% CI 0.97, 2.08; nominal P=0.164).

The main causes of death were disease progression (28 in the eltrombopag group and 21 in the placebo group) and sepsis (18 in the eltrombopag group and 13 in the placebo group).

Efficacy

The study’s primary endpoint was the proportion of patients free of platelet transfusions during cycles one to four of azacitidine therapy.

At the final analysis, there were fewer patients in the eltrombopag arm than in the placebo arm who had achieved platelet transfusion independence—16% (28/179) and 31% (55/177), respectively. The odds ratio (OR) was 0.37 (95% CI 0.21, 0.65; two-sided P value=0.001).

Secondary efficacy endpoints included overall survival, disease response, duration of response, progression to AML, progression-free survival, and hematologic improvement.

The investigators pointed out that no formal statistical tests were performed for the secondary endpoints. Therefore, “statistical interpretation should be made with caution,” they wrote.

Overall response by IWG criteria occurred in 20% of patients in the eltrombopag group and 35% of those in the placebo group, according to investigator assessment (OR=0.51; 95% CI 0.30, 0.86; nominal P=0.005).

There was no significant difference in hematologic improvement, overall survival, or progression-free survival between the treatment arms.

The investigators found a higher rate of progression to AML in the eltrombopag arm than in the placebo arm—15% and 9%, respectively (OR=1.59; 95% CI 0.81, 3.14; nominal P=0.079).

They pointed out that these results contrasted with those of recent clinical studies of eltrombopag monotherapy^1,2,3,4 in patients with MDS.

“[T]he findings of this trial were unexpected,” the investigators wrote.

They hypothesized that eltrombopag inhibits the effects of azacitidine when the drugs are given concomitantly. The issue is being studied further with ongoing research, they said.

The authors acknowledged financial support for medical editorial assistance provided by Novartis Pharmaceuticals Corporation.

Dr. Dickinson disclosed relationships with Celgene, Novartis, Janssen, Pfizer, and Roche. Senior study author Uwe Platzbecker, MD, disclosed relationships with Amgen, Celgene, GlaxoSmithKline, and Novartis.

1. Platzbecker U, et al Lancet Haematol. 2015;2(10):e417-e426. DOI: https://doi.org/10.1016/S2352-3026(15)00149-0

2. Oliva EN, et al. Lancet Haematol. 2017;4(3):e127-e136. DOI: https://doi.org/10.1016/S2352-3026(17)30012-1

3. Mittelman M, et al. Lancet Haematol. 2017;5(1):e34-e43. DOI: https://doi.org/10.1016/S2352-3026(17)30228-4

4. Buckstein R. Lancet Haematol. 2015;2(10):e396-e397. DOI: https://doi.org/10.1016/S2352-3026(15)00200-8

Photo courtesy of GSK

Results from the phase 3 SUPPORT trial suggest there is no role for the combination of eltrombopag and azacitidine in patients with intermediate- or high-risk myelodysplastic syndromes (MDS), according to investigators.

Adding eltrombopag to azacitidine worsened platelet recovery, reduced the overall response rate, and did not improve overall or progression-free survival when compared to azacitidine plus placebo.

Investigators had hypothesized that eltrombopag would reduce the thrombocytopenia exacerbated by azacitidine treatment.

Not only was this not the case, but the investigators observed a trend toward increased progression to acute myeloid leukemia (AML) in eltrombopag-treated patients.

An independent monitoring committee recommended the trial be terminated early.

Michael Dickinson, MBBS, of Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia, and his colleagues reported results from the trial in Blood.

The investigators conducted the SUPPORT study (NCT02158936) to investigate the efficacy and safety of eltrombopag as platelet supportive care in patients with intermediate- to high-risk MDS and thrombocytopenia who were receiving azacitidine.

Study design

Investigators randomized patients 1:1 to eltrombopag or placebo in combination with azacitidine. Patients had to have at least one platelet count less than 75 x 10⁹/L within 28 days prior to the first azacitidine dose.

Patients received azacitidine subcutaneously at a dose of 75 mg/m² once daily on 7 consecutive days for 28 days.

Patients received eltrombopag or placebo at a starting dose of 200 mg/day (100 mg/day for East Asians), adjusted by 100 mg increments (50 mg increments for East Asians) to a maximum of 300 mg/day (150 mg/day for East Asians).

Patient disposition

Investigators enrolled 356 patients from 30 countries between June 2014 and December 2015, randomizing 179 patients to eltrombopag and 177 to placebo.

Patients were a median age of 70, 66% were male, 83% were white, and 47% had platelet counts between 20 and 50 x 10⁹/L.

At the start of the trial, 19% of patients (n=66) were platelet transfusion-dependent—16% (29/179) in the eltrombopag group and 21% (37/177) in the placebo group.

Treatment exposure

Patients received eltrombopag for a median of 83 days (range, 60 to 148) and placebo for a median of 149 days (range, 8 to 503).

For non-East Asian patients, the mean dose of eltrombopag was 205 mg/day (range, 65 to 293), and the mean dose of placebo was 245 mg/day (range, 107 to 316).

Sixty-eight patients (38%) in the eltrombopag arm received the recommended number of six or more azacitidine cycles, compared to 91 (51%) in the placebo arm.

Two patients in the eltrombopag arm did not receive treatment. Therefore, the safety analyses were conducted on the 177 treated patients in each arm.

Safety

The most common reason for treatment discontinuation was termination of the study. Thirty-two percent of patients in the eltrombopag cohort and 44% in the placebo cohort discontinued for this reason.

Patients had to discontinue eltrombopag or placebo if azacitidine was discontinued, and this occurred in 30% of patients in the eltrombopag group and 26% in the placebo group.

Twenty-two percent of eltrombopag-treated patients discontinued due to adverse events (AEs), compared with 14% in the placebo group.

The most common reasons for azacitidine discontinuation in the eltrombopag and placebo arms, respectively, were study termination (35% and 46%), AEs (25% and 19%), disease progression (15% and 14%), and patient decision (11% and 9%).

AEs with the greatest difference between the eltrombopag and placebo arms, respectively, were febrile neutropenia (31% and 21%), neutropenia (31% and 26%), nausea (31% and 26%), and diarrhea (25% and 14%).

Sixty-three of the 177 AEs in the eltrombopag group were suspected to be treatment-related, compared to 42 of 173 AEs in the placebo group.

One hundred twenty-eight (72%) serious AEs occurred in the eltrombopag arm, compared to 100 (56%) in the placebo arm.

Fifteen percent of the serious AEs were suspected to be related to eltrombopag treatment, compared to 4% of the serious AEs in the placebo group.

At the final analysis, 108 patients had died—57 (32%) in the eltrombopag group and 51 (29%) in the placebo group (hazard ratio [HR] 1.42; 95% CI 0.97, 2.08; nominal P=0.164).

The main causes of death were disease progression (28 in the eltrombopag group and 21 in the placebo group) and sepsis (18 in the eltrombopag group and 13 in the placebo group).

Efficacy

The study’s primary endpoint was the proportion of patients free of platelet transfusions during cycles one to four of azacitidine therapy.

At the final analysis, there were fewer patients in the eltrombopag arm than in the placebo arm who had achieved platelet transfusion independence—16% (28/179) and 31% (55/177), respectively. The odds ratio (OR) was 0.37 (95% CI 0.21, 0.65; two-sided P value=0.001).

Secondary efficacy endpoints included overall survival, disease response, duration of response, progression to AML, progression-free survival, and hematologic improvement.

The investigators pointed out that no formal statistical tests were performed for the secondary endpoints. Therefore, “statistical interpretation should be made with caution,” they wrote.

Overall response by IWG criteria occurred in 20% of patients in the eltrombopag group and 35% of those in the placebo group, according to investigator assessment (OR=0.51; 95% CI 0.30, 0.86; nominal P=0.005).

There was no significant difference in hematologic improvement, overall survival, or progression-free survival between the treatment arms.

The investigators found a higher rate of progression to AML in the eltrombopag arm than in the placebo arm—15% and 9%, respectively (OR=1.59; 95% CI 0.81, 3.14; nominal P=0.079).

They pointed out that these results contrasted with those of recent clinical studies of eltrombopag monotherapy^1,2,3,4 in patients with MDS.

“[T]he findings of this trial were unexpected,” the investigators wrote.

They hypothesized that eltrombopag inhibits the effects of azacitidine when the drugs are given concomitantly. The issue is being studied further with ongoing research, they said.

The authors acknowledged financial support for medical editorial assistance provided by Novartis Pharmaceuticals Corporation.

Dr. Dickinson disclosed relationships with Celgene, Novartis, Janssen, Pfizer, and Roche. Senior study author Uwe Platzbecker, MD, disclosed relationships with Amgen, Celgene, GlaxoSmithKline, and Novartis.

1. Platzbecker U, et al Lancet Haematol. 2015;2(10):e417-e426. DOI: https://doi.org/10.1016/S2352-3026(15)00149-0

2. Oliva EN, et al. Lancet Haematol. 2017;4(3):e127-e136. DOI: https://doi.org/10.1016/S2352-3026(17)30012-1

3. Mittelman M, et al. Lancet Haematol. 2017;5(1):e34-e43. DOI: https://doi.org/10.1016/S2352-3026(17)30228-4

4. Buckstein R. Lancet Haematol. 2015;2(10):e396-e397. DOI: https://doi.org/10.1016/S2352-3026(15)00200-8

DUBROVNIK, CROATIA – Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).

However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

According to the 2016 WHO classification, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L), with monocytes accounting for 10% of the white blood cell count.
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
• They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.

If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.

However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
 

Differential diagnosis

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.

It can also be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
 

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).

However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻).
• Intermediate/MO2 (CD14^bright/CD16⁺).
• Nonclassical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.

She added that the technique can be implemented in clinical practice using the Hematoflow solution.

Dr. Durakovic did not report any conflicts of interest.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
 

[email protected]
 

DUBROVNIK, CROATIA – Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).

However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

According to the 2016 WHO classification, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L), with monocytes accounting for 10% of the white blood cell count.
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
• They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.

If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.

However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
 

Differential diagnosis

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.

It can also be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
 

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).

However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻).
• Intermediate/MO2 (CD14^bright/CD16⁺).
• Nonclassical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.

She added that the technique can be implemented in clinical practice using the Hematoflow solution.

Dr. Durakovic did not report any conflicts of interest.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
 

[email protected]
 

DUBROVNIK, CROATIA – Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).

However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

According to the 2016 WHO classification, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L), with monocytes accounting for 10% of the white blood cell count.
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
• They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.

If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.

However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
 

Differential diagnosis

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.

It can also be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
 

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).

However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻).
• Intermediate/MO2 (CD14^bright/CD16⁺).
• Nonclassical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.

She added that the technique can be implemented in clinical practice using the Hematoflow solution.

Dr. Durakovic did not report any conflicts of interest.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
 

[email protected]
 

Photo by Diane Reid

Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.

Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).

However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.

For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.

Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.

The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.

Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.

Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.

Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.

Factors associated with intense care

The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.

Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:

• Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
• Ages 30 to 39—OR=1.8 (P<0.01)
• Ages 40 to 49—OR=1.4 (P<0.05).

Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.

Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).

Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).

Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).

Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).

“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.

“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”

This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.

Photo by Diane Reid

Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.

Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).

However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.

For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.

Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.

The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.

Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.

Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.

Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.

Factors associated with intense care

The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.

Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:

• Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
• Ages 30 to 39—OR=1.8 (P<0.01)
• Ages 40 to 49—OR=1.4 (P<0.05).

Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.

Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).

Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).

Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).

Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).

“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.

“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”

This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.

Photo by Diane Reid

Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.

Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).

However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.

For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.

Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.

The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.

Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.

Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.

Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.

Factors associated with intense care

The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.

Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:

• Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
• Ages 30 to 39—OR=1.8 (P<0.01)
• Ages 40 to 49—OR=1.4 (P<0.05).

Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.

Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).

Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).

Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).

Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).

“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.

“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”

This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.

Micrograph showing MDS

Researchers have developed a new risk model for primary myelodysplastic syndromes (MDS) that integrates genetic and clinical information.

The research team considered the current standard for prognostication—the revised International Prognostic Scoring System (IPSS-R)—to be too complex, limited to newly diagnosed cases, and missing information on mutations and age.

So they devised a “simpler and more contemporary” prognostic system, the Mayo Alliance Prognostic Model for MDS.

The team, from the Mayo Clinic in Rochester, Minnesota, and the National Taiwan University Hospital (NTUH), described the new model in Mayo Clinic Proceedings.

Lead author Ayalew Tefferi, MD, of the Mayo Clinic, said the new model “is not an enhancement of the international prognostic scoring system tool, it's a complete makeover."

The team analyzed mutation information from 357 patients with primary MDS or leukemic transformation treated at the Mayo Clinic from the end of December 1994 through mid-December 2017.

The patients were a median age of 74 and 70% were males.

They compared the Mayo patients to 328 NTUH patients, who were a median age of 66 and 65% were males.

Multivariate analysis of the Mayo cohort identified the following as predictors of inferior overall survival:

• Monosomal karyotype (hazard ratio [HR], 5.2; 95% CI, 3.1-8.6)
• Non-monosomal karyotype abnormalities other than single/double del(5q) (HR, 1.8; 95% CI, 1.3-2.6)
• RUNX1 (HR, 2.0; 95% CI, 1.2-3.1)
• ASXL1 (HR, 1.7; 95% CI, 1.2-2.3) mutations
• Absence of SF3B1 mutations (HR, 1.6; 95% CI, 1.1-2.4)
• Age greater than 70 years (HR, 2.2; 95% CI, 1.6-3.1)
• Hemoglobin level less than 8 g/dL in women or less than 9 g/dL in men (HR, 2.3; 95% CI, 1.7-3.1)
• Platelet count less than 75 x 10⁹/L (HR, 1.5; 95% CI, 1.1-2.1)
• 10% or more bone marrow blasts (HR, 1.7; 95% CI, 1.1-2.8)

They then provided values to reflect the prognostic contribution of each of the above predictors and devised the new 4-tiered Mayo prognostic model.

Median 5-year overall survival rates in the 4 categories in the Mayo model were 73% (low risk), 34% (intermediate-1), 7% (intermediate-2), and 0% (high risk; 9-month median survival).

The team then validated the Mayo alliance model by using the NTUH cohort and compared it to the IPSS-R.

The investigators were able to confirm superior predictive accuracy of their model and a substantial discordance between the the Mayo model and the IPSS-R in terms of the pattern of risk distribution.

Examples of discordance included:

• More than 25% of patients belonging to the high-risk category according to the Mayo alliance model were classified as IPSS-R low or intermediate risk
• Almost 50% of patients with intermediate-2 risk category according to the Mayo alliance model were classified as IPSS-R very low or low risk
• Almost 50% of patients with IPSS-R very low risk were classified as intermediate-2 or intermediate-1 risk according to the Mayo alliance model

The authors wrote that this “suggests a fundamental and not incremental advantage for the new Mayo alliance model.” 

Micrograph showing MDS

Researchers have developed a new risk model for primary myelodysplastic syndromes (MDS) that integrates genetic and clinical information.

The research team considered the current standard for prognostication—the revised International Prognostic Scoring System (IPSS-R)—to be too complex, limited to newly diagnosed cases, and missing information on mutations and age.

So they devised a “simpler and more contemporary” prognostic system, the Mayo Alliance Prognostic Model for MDS.

The team, from the Mayo Clinic in Rochester, Minnesota, and the National Taiwan University Hospital (NTUH), described the new model in Mayo Clinic Proceedings.

Lead author Ayalew Tefferi, MD, of the Mayo Clinic, said the new model “is not an enhancement of the international prognostic scoring system tool, it's a complete makeover."

The team analyzed mutation information from 357 patients with primary MDS or leukemic transformation treated at the Mayo Clinic from the end of December 1994 through mid-December 2017.

The patients were a median age of 74 and 70% were males.

They compared the Mayo patients to 328 NTUH patients, who were a median age of 66 and 65% were males.

Multivariate analysis of the Mayo cohort identified the following as predictors of inferior overall survival:

• Monosomal karyotype (hazard ratio [HR], 5.2; 95% CI, 3.1-8.6)
• Non-monosomal karyotype abnormalities other than single/double del(5q) (HR, 1.8; 95% CI, 1.3-2.6)
• RUNX1 (HR, 2.0; 95% CI, 1.2-3.1)
• ASXL1 (HR, 1.7; 95% CI, 1.2-2.3) mutations
• Absence of SF3B1 mutations (HR, 1.6; 95% CI, 1.1-2.4)
• Age greater than 70 years (HR, 2.2; 95% CI, 1.6-3.1)
• Hemoglobin level less than 8 g/dL in women or less than 9 g/dL in men (HR, 2.3; 95% CI, 1.7-3.1)
• Platelet count less than 75 x 10⁹/L (HR, 1.5; 95% CI, 1.1-2.1)
• 10% or more bone marrow blasts (HR, 1.7; 95% CI, 1.1-2.8)

They then provided values to reflect the prognostic contribution of each of the above predictors and devised the new 4-tiered Mayo prognostic model.

Median 5-year overall survival rates in the 4 categories in the Mayo model were 73% (low risk), 34% (intermediate-1), 7% (intermediate-2), and 0% (high risk; 9-month median survival).

The team then validated the Mayo alliance model by using the NTUH cohort and compared it to the IPSS-R.

The investigators were able to confirm superior predictive accuracy of their model and a substantial discordance between the the Mayo model and the IPSS-R in terms of the pattern of risk distribution.

Examples of discordance included:

• More than 25% of patients belonging to the high-risk category according to the Mayo alliance model were classified as IPSS-R low or intermediate risk
• Almost 50% of patients with intermediate-2 risk category according to the Mayo alliance model were classified as IPSS-R very low or low risk
• Almost 50% of patients with IPSS-R very low risk were classified as intermediate-2 or intermediate-1 risk according to the Mayo alliance model

The authors wrote that this “suggests a fundamental and not incremental advantage for the new Mayo alliance model.” 

Micrograph showing MDS

Researchers have developed a new risk model for primary myelodysplastic syndromes (MDS) that integrates genetic and clinical information.

The research team considered the current standard for prognostication—the revised International Prognostic Scoring System (IPSS-R)—to be too complex, limited to newly diagnosed cases, and missing information on mutations and age.

So they devised a “simpler and more contemporary” prognostic system, the Mayo Alliance Prognostic Model for MDS.

The team, from the Mayo Clinic in Rochester, Minnesota, and the National Taiwan University Hospital (NTUH), described the new model in Mayo Clinic Proceedings.

Lead author Ayalew Tefferi, MD, of the Mayo Clinic, said the new model “is not an enhancement of the international prognostic scoring system tool, it's a complete makeover."

The team analyzed mutation information from 357 patients with primary MDS or leukemic transformation treated at the Mayo Clinic from the end of December 1994 through mid-December 2017.

The patients were a median age of 74 and 70% were males.

They compared the Mayo patients to 328 NTUH patients, who were a median age of 66 and 65% were males.

Multivariate analysis of the Mayo cohort identified the following as predictors of inferior overall survival:

• Monosomal karyotype (hazard ratio [HR], 5.2; 95% CI, 3.1-8.6)
• Non-monosomal karyotype abnormalities other than single/double del(5q) (HR, 1.8; 95% CI, 1.3-2.6)
• RUNX1 (HR, 2.0; 95% CI, 1.2-3.1)
• ASXL1 (HR, 1.7; 95% CI, 1.2-2.3) mutations
• Absence of SF3B1 mutations (HR, 1.6; 95% CI, 1.1-2.4)
• Age greater than 70 years (HR, 2.2; 95% CI, 1.6-3.1)
• Hemoglobin level less than 8 g/dL in women or less than 9 g/dL in men (HR, 2.3; 95% CI, 1.7-3.1)
• Platelet count less than 75 x 10⁹/L (HR, 1.5; 95% CI, 1.1-2.1)
• 10% or more bone marrow blasts (HR, 1.7; 95% CI, 1.1-2.8)

They then provided values to reflect the prognostic contribution of each of the above predictors and devised the new 4-tiered Mayo prognostic model.

Median 5-year overall survival rates in the 4 categories in the Mayo model were 73% (low risk), 34% (intermediate-1), 7% (intermediate-2), and 0% (high risk; 9-month median survival).

The team then validated the Mayo alliance model by using the NTUH cohort and compared it to the IPSS-R.

The investigators were able to confirm superior predictive accuracy of their model and a substantial discordance between the the Mayo model and the IPSS-R in terms of the pattern of risk distribution.

Examples of discordance included:

• More than 25% of patients belonging to the high-risk category according to the Mayo alliance model were classified as IPSS-R low or intermediate risk
• Almost 50% of patients with intermediate-2 risk category according to the Mayo alliance model were classified as IPSS-R very low or low risk
• Almost 50% of patients with IPSS-R very low risk were classified as intermediate-2 or intermediate-1 risk according to the Mayo alliance model

The authors wrote that this “suggests a fundamental and not incremental advantage for the new Mayo alliance model.” 

Photo by Chad McNeeley

Gene sequencing early after transplant may provide important prognostic information in patients with myelodysplastic syndromes (MDS), according to a new study.

Patients who had disease-associated mutations in the bone marrow 30 days after hematopoietic stem cell transplant (HSCT) were significantly more likely to experience disease progression and have lower rates of progression-free survival (PFS) at 1 year.

“Using our sequencing method, we’re identifying residual tumor cells before a pathologist could see them under the microscope and before a patient develops symptoms,” said Matthew J. Walter, MD, of Washington University in St. Louis, Mo.

“At that moment, there may be time to intervene in ways that could delay the cancer from coming back or potentially prevent it completely.”

Dr. Walter and his colleagues described results with their sequencing method in The New England Journal of Medicine.

The researchers sequenced bone marrow and skin (control) samples from 90 adults with MDS who underwent allogeneic HSCT.

The team used enhanced exome sequencing to detect mutations before HSCT and evaluated mutation clearance using error-corrected sequencing to genotype mutations in bone marrow samples collected 30 days after HSCT.

The researchers detected at least one validated somatic mutation in the pre-HSCT samples from 86 of 90 patients.

Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after HSCT. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the researchers explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not progress (P<0.001).

Progression occurred in 53.1% of patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days, whereas progression occurred in 13% of patients who did not have such mutations. After adjusting for conditioning regimen, the hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P<0.001).

The 1-year PFS rate was 31.3% in patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days and 59.3% in patients who did not have the mutations. After adjusting for conditioning, the HR for progression or death was 2.22 (P=0.005).

The researchers noted that PFS was lower in patients who had received reduced-intensity conditioning and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 (P≤0.001), when compared to other combinations of conditioning regimen and mutation status.

In multivariable analyses, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than four-fold risk of progression (HR, 4.48; P<0.001) and a more than two-fold risk of progression or death (HR, 2.39; P=0.002).

“Now that we have detected mutations early and shown that it predicts a higher risk of recurrence, we want to determine the best course of action for those high-risk patients,” Dr. Walter said.

He and his colleagues acknowledged that the high-coverage exome sequencing technique used for this study is not routinely available in the clinic. Therefore, the researchers also analyzed samples using a subset of genes that are usually included in gene sequencing panels for MDS and acute myeloid leukemia.

The researchers noted that this 40-gene panel revealed fewer patients (n=68; 79%) with mutations, but “the prognostic value of detection of measurable residual disease was still highly clinically significant.”

With this approach, the presence of at least one mutation with a variant allele frequency of at least 0.5% 30 days after HSCT was associated with a higher risk of disease progression at 1 year (HR, 3.39; P=0.001) and a higher risk of progression or death at 1 year (HR, 2.09; P=0.02).

This study was supported by grants from the Leukemia and Lymphoma Society and other groups.

Photo by Chad McNeeley

Gene sequencing early after transplant may provide important prognostic information in patients with myelodysplastic syndromes (MDS), according to a new study.

Patients who had disease-associated mutations in the bone marrow 30 days after hematopoietic stem cell transplant (HSCT) were significantly more likely to experience disease progression and have lower rates of progression-free survival (PFS) at 1 year.

“Using our sequencing method, we’re identifying residual tumor cells before a pathologist could see them under the microscope and before a patient develops symptoms,” said Matthew J. Walter, MD, of Washington University in St. Louis, Mo.

“At that moment, there may be time to intervene in ways that could delay the cancer from coming back or potentially prevent it completely.”

Dr. Walter and his colleagues described results with their sequencing method in The New England Journal of Medicine.

The researchers sequenced bone marrow and skin (control) samples from 90 adults with MDS who underwent allogeneic HSCT.

The team used enhanced exome sequencing to detect mutations before HSCT and evaluated mutation clearance using error-corrected sequencing to genotype mutations in bone marrow samples collected 30 days after HSCT.

The researchers detected at least one validated somatic mutation in the pre-HSCT samples from 86 of 90 patients.

Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after HSCT. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the researchers explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not progress (P<0.001).

Progression occurred in 53.1% of patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days, whereas progression occurred in 13% of patients who did not have such mutations. After adjusting for conditioning regimen, the hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P<0.001).

The 1-year PFS rate was 31.3% in patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days and 59.3% in patients who did not have the mutations. After adjusting for conditioning, the HR for progression or death was 2.22 (P=0.005).

The researchers noted that PFS was lower in patients who had received reduced-intensity conditioning and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 (P≤0.001), when compared to other combinations of conditioning regimen and mutation status.

In multivariable analyses, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than four-fold risk of progression (HR, 4.48; P<0.001) and a more than two-fold risk of progression or death (HR, 2.39; P=0.002).

“Now that we have detected mutations early and shown that it predicts a higher risk of recurrence, we want to determine the best course of action for those high-risk patients,” Dr. Walter said.

He and his colleagues acknowledged that the high-coverage exome sequencing technique used for this study is not routinely available in the clinic. Therefore, the researchers also analyzed samples using a subset of genes that are usually included in gene sequencing panels for MDS and acute myeloid leukemia.

The researchers noted that this 40-gene panel revealed fewer patients (n=68; 79%) with mutations, but “the prognostic value of detection of measurable residual disease was still highly clinically significant.”

With this approach, the presence of at least one mutation with a variant allele frequency of at least 0.5% 30 days after HSCT was associated with a higher risk of disease progression at 1 year (HR, 3.39; P=0.001) and a higher risk of progression or death at 1 year (HR, 2.09; P=0.02).

This study was supported by grants from the Leukemia and Lymphoma Society and other groups.

Photo by Chad McNeeley

Gene sequencing early after transplant may provide important prognostic information in patients with myelodysplastic syndromes (MDS), according to a new study.

Patients who had disease-associated mutations in the bone marrow 30 days after hematopoietic stem cell transplant (HSCT) were significantly more likely to experience disease progression and have lower rates of progression-free survival (PFS) at 1 year.

“Using our sequencing method, we’re identifying residual tumor cells before a pathologist could see them under the microscope and before a patient develops symptoms,” said Matthew J. Walter, MD, of Washington University in St. Louis, Mo.

“At that moment, there may be time to intervene in ways that could delay the cancer from coming back or potentially prevent it completely.”

Dr. Walter and his colleagues described results with their sequencing method in The New England Journal of Medicine.

The researchers sequenced bone marrow and skin (control) samples from 90 adults with MDS who underwent allogeneic HSCT.

The team used enhanced exome sequencing to detect mutations before HSCT and evaluated mutation clearance using error-corrected sequencing to genotype mutations in bone marrow samples collected 30 days after HSCT.

The researchers detected at least one validated somatic mutation in the pre-HSCT samples from 86 of 90 patients.

Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after HSCT. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the researchers explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not progress (P<0.001).

Progression occurred in 53.1% of patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days, whereas progression occurred in 13% of patients who did not have such mutations. After adjusting for conditioning regimen, the hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P<0.001).

The 1-year PFS rate was 31.3% in patients who had one or more mutations with a variant allele frequency of at least 0.5% at 30 days and 59.3% in patients who did not have the mutations. After adjusting for conditioning, the HR for progression or death was 2.22 (P=0.005).

The researchers noted that PFS was lower in patients who had received reduced-intensity conditioning and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 (P≤0.001), when compared to other combinations of conditioning regimen and mutation status.

In multivariable analyses, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than four-fold risk of progression (HR, 4.48; P<0.001) and a more than two-fold risk of progression or death (HR, 2.39; P=0.002).

“Now that we have detected mutations early and shown that it predicts a higher risk of recurrence, we want to determine the best course of action for those high-risk patients,” Dr. Walter said.

He and his colleagues acknowledged that the high-coverage exome sequencing technique used for this study is not routinely available in the clinic. Therefore, the researchers also analyzed samples using a subset of genes that are usually included in gene sequencing panels for MDS and acute myeloid leukemia.

The researchers noted that this 40-gene panel revealed fewer patients (n=68; 79%) with mutations, but “the prognostic value of detection of measurable residual disease was still highly clinically significant.”

With this approach, the presence of at least one mutation with a variant allele frequency of at least 0.5% 30 days after HSCT was associated with a higher risk of disease progression at 1 year (HR, 3.39; P=0.001) and a higher risk of progression or death at 1 year (HR, 2.09; P=0.02).

This study was supported by grants from the Leukemia and Lymphoma Society and other groups.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Lab mouse

The transcription factor HIF1A could be a therapeutic target for “a broad spectrum” of patients with myelodysplastic syndromes (MDS), according to researchers.

Preclinical experiments indicated that HIF1A fuels the biological processes that cause different types of MDS.

Researchers also found that inhibiting HIF1A reversed MDS symptoms and prolonged survival in mouse models of MDS.

Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Cancer Discovery.

The researchers identified HIF1A’s role in MDS by first analyzing cells from healthy donors and MDS patients, including patients with refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess blasts type 1 and 2.

The researchers observed increased gene expression of HIF1A-induced genes in the cells from MDS patients. The team also found a high frequency of HIF1A-expressing cells in the MDS cohort, regardless of the patients’ IPSS-R risk.

The researchers conducted experiments in mouse models to study the onset of MDS and its genetic and molecular drivers. The results suggested that dysregulation of HIF1A has a central role in the onset of MDS, including different manifestations and symptoms found in patients.

“We know the genomes of MDS patients have recurrent mutations in different transcriptional, epigenetic, and metabolic regulators, but the incidence of these mutations does not directly correspond to the disease when it occurs,” Dr. Huang noted.

“Our study shows that malfunctions in the signaling of HIF1A could be generating the diverse medical problems doctors see in MDS patients.”

Specifically, the researchers found that MDS-associated mutations—DNMT3A, TET2, ASXL1, RUNX1, and MLL1—induced HIF1A signaling. And activation of HIF1A signaling in hematopoietic cells induced MDS phenotypes in mice.

The team said this suggests dysregulation of HIF1A signaling could generate diverse MDS phenotypes by “functioning as a signaling funnel” for MDS driver mutations.

The researchers also showed that inhibition of HIF1A could reverse MDS phenotypes. They said HIF1A deletion rescued dysplasia formation, partially rescued thrombocytopenia, and abrogated MDS development in mouse models.

Treatment with echinomycin, an inhibitor of HIF1A-mediated target gene activation, prolonged survival in mouse models of MDS and decreased MDSL cell numbers in the bone marrow and spleen.

This research was supported by the Kyoto University Foundation, the MDS Foundation, the Cincinnati Children’s Hospital Research Foundation, the Leukemia Research Foundation, and others.

Lab mouse

The transcription factor HIF1A could be a therapeutic target for “a broad spectrum” of patients with myelodysplastic syndromes (MDS), according to researchers.

Preclinical experiments indicated that HIF1A fuels the biological processes that cause different types of MDS.

Researchers also found that inhibiting HIF1A reversed MDS symptoms and prolonged survival in mouse models of MDS.

Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Cancer Discovery.

The researchers identified HIF1A’s role in MDS by first analyzing cells from healthy donors and MDS patients, including patients with refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess blasts type 1 and 2.

The researchers observed increased gene expression of HIF1A-induced genes in the cells from MDS patients. The team also found a high frequency of HIF1A-expressing cells in the MDS cohort, regardless of the patients’ IPSS-R risk.

The researchers conducted experiments in mouse models to study the onset of MDS and its genetic and molecular drivers. The results suggested that dysregulation of HIF1A has a central role in the onset of MDS, including different manifestations and symptoms found in patients.

“We know the genomes of MDS patients have recurrent mutations in different transcriptional, epigenetic, and metabolic regulators, but the incidence of these mutations does not directly correspond to the disease when it occurs,” Dr. Huang noted.

“Our study shows that malfunctions in the signaling of HIF1A could be generating the diverse medical problems doctors see in MDS patients.”

Specifically, the researchers found that MDS-associated mutations—DNMT3A, TET2, ASXL1, RUNX1, and MLL1—induced HIF1A signaling. And activation of HIF1A signaling in hematopoietic cells induced MDS phenotypes in mice.

The team said this suggests dysregulation of HIF1A signaling could generate diverse MDS phenotypes by “functioning as a signaling funnel” for MDS driver mutations.

The researchers also showed that inhibition of HIF1A could reverse MDS phenotypes. They said HIF1A deletion rescued dysplasia formation, partially rescued thrombocytopenia, and abrogated MDS development in mouse models.

Treatment with echinomycin, an inhibitor of HIF1A-mediated target gene activation, prolonged survival in mouse models of MDS and decreased MDSL cell numbers in the bone marrow and spleen.

This research was supported by the Kyoto University Foundation, the MDS Foundation, the Cincinnati Children’s Hospital Research Foundation, the Leukemia Research Foundation, and others.

Lab mouse

The transcription factor HIF1A could be a therapeutic target for “a broad spectrum” of patients with myelodysplastic syndromes (MDS), according to researchers.

Preclinical experiments indicated that HIF1A fuels the biological processes that cause different types of MDS.

Researchers also found that inhibiting HIF1A reversed MDS symptoms and prolonged survival in mouse models of MDS.

Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio, and his colleagues reported these findings in Cancer Discovery.

The researchers identified HIF1A’s role in MDS by first analyzing cells from healthy donors and MDS patients, including patients with refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess blasts type 1 and 2.

The researchers observed increased gene expression of HIF1A-induced genes in the cells from MDS patients. The team also found a high frequency of HIF1A-expressing cells in the MDS cohort, regardless of the patients’ IPSS-R risk.

The researchers conducted experiments in mouse models to study the onset of MDS and its genetic and molecular drivers. The results suggested that dysregulation of HIF1A has a central role in the onset of MDS, including different manifestations and symptoms found in patients.

“We know the genomes of MDS patients have recurrent mutations in different transcriptional, epigenetic, and metabolic regulators, but the incidence of these mutations does not directly correspond to the disease when it occurs,” Dr. Huang noted.

“Our study shows that malfunctions in the signaling of HIF1A could be generating the diverse medical problems doctors see in MDS patients.”

Specifically, the researchers found that MDS-associated mutations—DNMT3A, TET2, ASXL1, RUNX1, and MLL1—induced HIF1A signaling. And activation of HIF1A signaling in hematopoietic cells induced MDS phenotypes in mice.

The team said this suggests dysregulation of HIF1A signaling could generate diverse MDS phenotypes by “functioning as a signaling funnel” for MDS driver mutations.

The researchers also showed that inhibition of HIF1A could reverse MDS phenotypes. They said HIF1A deletion rescued dysplasia formation, partially rescued thrombocytopenia, and abrogated MDS development in mouse models.

Treatment with echinomycin, an inhibitor of HIF1A-mediated target gene activation, prolonged survival in mouse models of MDS and decreased MDSL cell numbers in the bone marrow and spleen.

This research was supported by the Kyoto University Foundation, the MDS Foundation, the Cincinnati Children’s Hospital Research Foundation, the Leukemia Research Foundation, and others.

Image courtesy of AFIP

A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).

The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.

The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.

The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.

“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.

“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”

The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.

However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.

AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.

The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.

“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.

Image courtesy of AFIP

A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).

The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.

The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.

The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.

“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.

“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”

The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.

However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.

AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.

The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.

“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.

Image courtesy of AFIP

A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).

The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.

The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.

The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.

“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.

“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”

The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.

However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.

AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.

The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.

“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.

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.