CML

Micrograph showing CML

Image by Difu Wu

The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.

The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).

The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.

Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.

Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.

However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.

Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.

Problems with ponatinib

Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.

In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.

That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.

EPIC trial

The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.

The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.

Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.

Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).

The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).

All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.

Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).

Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).

Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.

Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.

The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.

Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.

Micrograph showing CML

Image by Difu Wu

The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.

The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).

The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.

Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.

Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.

However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.

Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.

Problems with ponatinib

Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.

In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.

That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.

EPIC trial

The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.

The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.

Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.

Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).

The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).

All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.

Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).

Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).

Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.

Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.

The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.

Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.

Micrograph showing CML

Image by Difu Wu

The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.

The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).

The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.

Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.

Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.

However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.

Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.

Problems with ponatinib

Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.

In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.

That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.

EPIC trial

The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.

The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.

Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.

Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).

The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).

All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.

Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).

Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).

Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.

Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.

The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.

Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.

Patients with newly diagnosed chronic lymphocytic leukemia should standardly undergo immunoglobulin heavy-chain variable region gene (IGHV) mutation status and interphase fluorescence in situ hybridization (FISH) tests, based on the results of a meta-analysis published in Blood.

“This change will help define the minimal standard initial prognostic evaluation for patients with CLL and help facilitate use of the powerful, recently developed, integrated prognostic indices, all of which are dependent on these 2 variables,” wrote Dr. Sameer A. Parikh of Mayo Clinic, Rochester, Minn., and associates.

By Gregor1976 via Wikimedia Commons

IGHV and FISH have prognostic value independent of clinical stage in patients with newly diagnosed and previously untreated CLL, they said (Blood. 2016;127[14]:1752-60). Better understanding of the patient’s risk of disease progression at diagnosis can guide counseling and follow-up intervals, and could potentially influence the decision to treat high-risk patients on early intervention protocols.

IGHV and FISH also appear to provide additional information on progression-free and overall survival.

The researchers cautioned, however, that the results of these tests should not be used to initiate CLL-specific therapy. Only patients who meet indications for therapy based on the 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines should receive treatment.

Further, they noted, the median age of patients included in studies that they analyzed was 64 years; the median age of patients with CLL is 72 years. The prognostic abilities of IGHV mutation and FISH may differ in these older individuals with CLL.

The researchers analyzed 31 studies that met the criteria for inclusion – full-length publications that included at least 200 patients and reported on the prognostic value of IGHV and/or FISH for predicting progression-free or overall survival in patients with newly diagnosed CLL.

They found that the median progression-free survival (range, about 1-5 years) was significantly shorter for patients with unmutated IGHV genes, than was the median progression-free survival (range, about 9-19 years) for those with mutated IGHV genes. Similarly, the median overall survival was significantly shorter for patients with unmutated IGHV (range, about 3-10 years) than for those with mutated IGHV (range, about 18-26 years).

For patients with high-risk FISH (including del17p13 and del11q23), the median progression-free survival was significantly shorter (range, about 0.1-5 years) than for those with low/intermediate-risk FISH (including del13q, normal, and trisomy 12; range, about 1.5-22 years). Median overall survival also significantly differed, ranging from about 3-10 years for patients with high-risk FISH and from about 7.5-20.5 years for those with low/intermediate-risk FISH.

In multivariable analyses, the hazard ratio for high-risk FISH ranged from 1.3 to 4.7 for progression-free survival and from 0.9 to 8.2 for overall survival. In studies reporting the results of multivariable analysis, high-risk FISH remained an independent predictor of progression-free survival in 8 of 17 studies and of overall survival in 10 of 14 studies, including in 10 of 13 studies adjusting for the prognostic impact of IGHV.

In multivariable analyses, IGHV remained an independent predictor of progression-free survival in 15 of 18 studies, including 12 of 15 studies adjusting for the prognostic impact of FISH. IGHV remained an independent predictor of overall survival in 11 of 15 studies reporting the results of multivariable analysis, including 10 of 14 studies adjusting for the prognostic impact of FISH.

Patients with newly diagnosed chronic lymphocytic leukemia should standardly undergo immunoglobulin heavy-chain variable region gene (IGHV) mutation status and interphase fluorescence in situ hybridization (FISH) tests, based on the results of a meta-analysis published in Blood.

“This change will help define the minimal standard initial prognostic evaluation for patients with CLL and help facilitate use of the powerful, recently developed, integrated prognostic indices, all of which are dependent on these 2 variables,” wrote Dr. Sameer A. Parikh of Mayo Clinic, Rochester, Minn., and associates.

By Gregor1976 via Wikimedia Commons

IGHV and FISH have prognostic value independent of clinical stage in patients with newly diagnosed and previously untreated CLL, they said (Blood. 2016;127[14]:1752-60). Better understanding of the patient’s risk of disease progression at diagnosis can guide counseling and follow-up intervals, and could potentially influence the decision to treat high-risk patients on early intervention protocols.

IGHV and FISH also appear to provide additional information on progression-free and overall survival.

The researchers cautioned, however, that the results of these tests should not be used to initiate CLL-specific therapy. Only patients who meet indications for therapy based on the 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines should receive treatment.

Further, they noted, the median age of patients included in studies that they analyzed was 64 years; the median age of patients with CLL is 72 years. The prognostic abilities of IGHV mutation and FISH may differ in these older individuals with CLL.

The researchers analyzed 31 studies that met the criteria for inclusion – full-length publications that included at least 200 patients and reported on the prognostic value of IGHV and/or FISH for predicting progression-free or overall survival in patients with newly diagnosed CLL.

They found that the median progression-free survival (range, about 1-5 years) was significantly shorter for patients with unmutated IGHV genes, than was the median progression-free survival (range, about 9-19 years) for those with mutated IGHV genes. Similarly, the median overall survival was significantly shorter for patients with unmutated IGHV (range, about 3-10 years) than for those with mutated IGHV (range, about 18-26 years).

For patients with high-risk FISH (including del17p13 and del11q23), the median progression-free survival was significantly shorter (range, about 0.1-5 years) than for those with low/intermediate-risk FISH (including del13q, normal, and trisomy 12; range, about 1.5-22 years). Median overall survival also significantly differed, ranging from about 3-10 years for patients with high-risk FISH and from about 7.5-20.5 years for those with low/intermediate-risk FISH.

In multivariable analyses, the hazard ratio for high-risk FISH ranged from 1.3 to 4.7 for progression-free survival and from 0.9 to 8.2 for overall survival. In studies reporting the results of multivariable analysis, high-risk FISH remained an independent predictor of progression-free survival in 8 of 17 studies and of overall survival in 10 of 14 studies, including in 10 of 13 studies adjusting for the prognostic impact of IGHV.

In multivariable analyses, IGHV remained an independent predictor of progression-free survival in 15 of 18 studies, including 12 of 15 studies adjusting for the prognostic impact of FISH. IGHV remained an independent predictor of overall survival in 11 of 15 studies reporting the results of multivariable analysis, including 10 of 14 studies adjusting for the prognostic impact of FISH.

Patients with newly diagnosed chronic lymphocytic leukemia should standardly undergo immunoglobulin heavy-chain variable region gene (IGHV) mutation status and interphase fluorescence in situ hybridization (FISH) tests, based on the results of a meta-analysis published in Blood.

“This change will help define the minimal standard initial prognostic evaluation for patients with CLL and help facilitate use of the powerful, recently developed, integrated prognostic indices, all of which are dependent on these 2 variables,” wrote Dr. Sameer A. Parikh of Mayo Clinic, Rochester, Minn., and associates.

By Gregor1976 via Wikimedia Commons

IGHV and FISH have prognostic value independent of clinical stage in patients with newly diagnosed and previously untreated CLL, they said (Blood. 2016;127[14]:1752-60). Better understanding of the patient’s risk of disease progression at diagnosis can guide counseling and follow-up intervals, and could potentially influence the decision to treat high-risk patients on early intervention protocols.

IGHV and FISH also appear to provide additional information on progression-free and overall survival.

The researchers cautioned, however, that the results of these tests should not be used to initiate CLL-specific therapy. Only patients who meet indications for therapy based on the 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines should receive treatment.

Further, they noted, the median age of patients included in studies that they analyzed was 64 years; the median age of patients with CLL is 72 years. The prognostic abilities of IGHV mutation and FISH may differ in these older individuals with CLL.

The researchers analyzed 31 studies that met the criteria for inclusion – full-length publications that included at least 200 patients and reported on the prognostic value of IGHV and/or FISH for predicting progression-free or overall survival in patients with newly diagnosed CLL.

They found that the median progression-free survival (range, about 1-5 years) was significantly shorter for patients with unmutated IGHV genes, than was the median progression-free survival (range, about 9-19 years) for those with mutated IGHV genes. Similarly, the median overall survival was significantly shorter for patients with unmutated IGHV (range, about 3-10 years) than for those with mutated IGHV (range, about 18-26 years).

For patients with high-risk FISH (including del17p13 and del11q23), the median progression-free survival was significantly shorter (range, about 0.1-5 years) than for those with low/intermediate-risk FISH (including del13q, normal, and trisomy 12; range, about 1.5-22 years). Median overall survival also significantly differed, ranging from about 3-10 years for patients with high-risk FISH and from about 7.5-20.5 years for those with low/intermediate-risk FISH.

In multivariable analyses, the hazard ratio for high-risk FISH ranged from 1.3 to 4.7 for progression-free survival and from 0.9 to 8.2 for overall survival. In studies reporting the results of multivariable analysis, high-risk FISH remained an independent predictor of progression-free survival in 8 of 17 studies and of overall survival in 10 of 14 studies, including in 10 of 13 studies adjusting for the prognostic impact of IGHV.

In multivariable analyses, IGHV remained an independent predictor of progression-free survival in 15 of 18 studies, including 12 of 15 studies adjusting for the prognostic impact of FISH. IGHV remained an independent predictor of overall survival in 11 of 15 studies reporting the results of multivariable analysis, including 10 of 14 studies adjusting for the prognostic impact of FISH.

Federal officials took the next step in their moonshot to end cancer by announcing on April 4 a blue ribbon panel to guide the effort.

A total of 28 leading researchers, clinicians, and patient advocates have been named to the panel charged with informing the scientific direction and goals of the National Cancer Moonshot Initiative, led by Vice President Joe Biden.

“This Blue Ribbon Panel will ensure that, as [the National Institutes of Health] allocates new resources through the Moonshot, decisions will be grounded in the best science,” Vice President Biden said in a statement. “I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer.”

The key goals of the initiative were set out simultaneously in a perspective from Dr. Francis S. Collins, NIH director, and Dr. Douglas R. Lowy, director of the National Cancer Institute. The editorial was published in the New England Journal of Medicine.

“Fueled by an additional $680 million in the proposed fiscal year 2017 budget for the NIH, plus additional resources for the Food and Drug Administration, the initiative will aim to accelerate progress toward the next generation of interventions that we hope will substantially reduce cancer incidence and dramatically improve patient outcomes,” Dr. Collins and Dr. Lowy wrote. “The NIH’s most compelling opportunities for progress will be set forth by late summer 2016 in a research plan informed by the deliberations of a blue-ribbon panel of experts, which will provide scientific input to the National Cancer Advisory Board. Some possible opportunities include vaccine development, early-detection technology, single-cell genomic analysis, immunotherapy, a focus on pediatric cancer, and enhanced data sharing.”

To read the full editorial, click here.

[email protected]

On Twitter @denisefulton

Federal officials took the next step in their moonshot to end cancer by announcing on April 4 a blue ribbon panel to guide the effort.

A total of 28 leading researchers, clinicians, and patient advocates have been named to the panel charged with informing the scientific direction and goals of the National Cancer Moonshot Initiative, led by Vice President Joe Biden.

“This Blue Ribbon Panel will ensure that, as [the National Institutes of Health] allocates new resources through the Moonshot, decisions will be grounded in the best science,” Vice President Biden said in a statement. “I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer.”

The key goals of the initiative were set out simultaneously in a perspective from Dr. Francis S. Collins, NIH director, and Dr. Douglas R. Lowy, director of the National Cancer Institute. The editorial was published in the New England Journal of Medicine.

“Fueled by an additional $680 million in the proposed fiscal year 2017 budget for the NIH, plus additional resources for the Food and Drug Administration, the initiative will aim to accelerate progress toward the next generation of interventions that we hope will substantially reduce cancer incidence and dramatically improve patient outcomes,” Dr. Collins and Dr. Lowy wrote. “The NIH’s most compelling opportunities for progress will be set forth by late summer 2016 in a research plan informed by the deliberations of a blue-ribbon panel of experts, which will provide scientific input to the National Cancer Advisory Board. Some possible opportunities include vaccine development, early-detection technology, single-cell genomic analysis, immunotherapy, a focus on pediatric cancer, and enhanced data sharing.”

To read the full editorial, click here.

[email protected]

On Twitter @denisefulton

Federal officials took the next step in their moonshot to end cancer by announcing on April 4 a blue ribbon panel to guide the effort.

A total of 28 leading researchers, clinicians, and patient advocates have been named to the panel charged with informing the scientific direction and goals of the National Cancer Moonshot Initiative, led by Vice President Joe Biden.

“This Blue Ribbon Panel will ensure that, as [the National Institutes of Health] allocates new resources through the Moonshot, decisions will be grounded in the best science,” Vice President Biden said in a statement. “I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer.”

The key goals of the initiative were set out simultaneously in a perspective from Dr. Francis S. Collins, NIH director, and Dr. Douglas R. Lowy, director of the National Cancer Institute. The editorial was published in the New England Journal of Medicine.

“Fueled by an additional $680 million in the proposed fiscal year 2017 budget for the NIH, plus additional resources for the Food and Drug Administration, the initiative will aim to accelerate progress toward the next generation of interventions that we hope will substantially reduce cancer incidence and dramatically improve patient outcomes,” Dr. Collins and Dr. Lowy wrote. “The NIH’s most compelling opportunities for progress will be set forth by late summer 2016 in a research plan informed by the deliberations of a blue-ribbon panel of experts, which will provide scientific input to the National Cancer Advisory Board. Some possible opportunities include vaccine development, early-detection technology, single-cell genomic analysis, immunotherapy, a focus on pediatric cancer, and enhanced data sharing.”

To read the full editorial, click here.

[email protected]

On Twitter @denisefulton

High-dose cyclophosphamide is safe and effective when given as prophylaxis for chronic graft-versus-host disease (GVHD) to patients who have undergone transplantation of mobilized blood cells, finds a phase 2 trial reported in Blood.

Investigators led by Dr. Marco Mielcarek, medical director of the Adult Blood and Marrow Transplant Program and an oncologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, enrolled in the trial 43 patients with high-risk hematologic malignancies.

The patients underwent myeloablative conditioning followed by transplantation with growth factor–mobilized blood cells from related or unrelated donors, and were given high-dose cyclophosphamide on two early posttransplantation days.

Main results showed that the cumulative 1-year incidence of chronic GVHD was 16%, less than half of the roughly 35% seen historically with conventional immunosuppression.

Moreover, cyclophosphamide did not appear to compromise engraftment or control of the underlying malignancy. Only a single patient, one with an HLA-mismatched donor, had failure of primary engraftment; after amendment of the protocol to require HLA matching, there were no additional cases. Just 17% of patients experienced a recurrence of their malignancy by 2 years.

Taken together, the findings suggest that high-dose cyclophosphamide—as combined with two myeloablative conditioning options (to accommodate different malignancies) and with posttransplantation cyclosporine (to reduce the risk of acute GVHD)—may eliminate most of the drawbacks to using mobilized blood cells for transplantation, according to the investigators.

“If these findings are confirmed in future studies, HLA-matched mobilized blood cell transplantation may gain even greater acceptance and further replace marrow as a source of stem cells for most indications,” they maintain.

The patients studied had a median age of 43 years, and slightly more than half were in remission without minimal residual disease.

Blood cells were mobilized with granulocyte colony-stimulating factor (G-CSF). Overall, 28% of patients received grafts from related donors, while 72% received grafts from unrelated donors.

For pretransplant conditioning, patients received fludarabine and targeted busulfan, or total body irradiation with use of a minimum dose of 12 Gy.

The patients were given cyclophosphamide at 50 mg/kg per day on days 3 and 4 after transplantation. This was followed by cyclosporine starting on day 5.

The cumulative 1-year incidence of chronic GVHD as defined by National Institutes of Health criteria (i.e., that requiring systemic immunosuppressive therapy)—the trial’s primary endpoint—was 16%, which fell just short of the goal of 15% the investigators were aiming for (Blood. 2016;127:1502-8). Analyses failed to identify any predictors of this outcome.

Although the estimated cumulative incidence of grade 2 acute GVHD was high, at 77%, none of the patients developed grade 3 or 4 acute GVHD, according to the investigators, who disclosed that they had no competing financial interests.

The single patient who experienced failure of primary engraftment had familial myelodysplastic syndrome and had received a graft from an HLA A-antigen–mismatched unrelated donor.

The 2-year cumulative incidence of nonrelapse mortality was 14%, and the 2-year cumulative incidence of recurrent malignancy was 17%. Projected overall survival was 70%.

Among the 42 patients having at least a year of follow-up, 50% were alive and free of relapse without any systemic immunosuppression at 1 year after transplantation.

High-dose cyclophosphamide is safe and effective when given as prophylaxis for chronic graft-versus-host disease (GVHD) to patients who have undergone transplantation of mobilized blood cells, finds a phase 2 trial reported in Blood.

Investigators led by Dr. Marco Mielcarek, medical director of the Adult Blood and Marrow Transplant Program and an oncologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, enrolled in the trial 43 patients with high-risk hematologic malignancies.

The patients underwent myeloablative conditioning followed by transplantation with growth factor–mobilized blood cells from related or unrelated donors, and were given high-dose cyclophosphamide on two early posttransplantation days.

Main results showed that the cumulative 1-year incidence of chronic GVHD was 16%, less than half of the roughly 35% seen historically with conventional immunosuppression.

Moreover, cyclophosphamide did not appear to compromise engraftment or control of the underlying malignancy. Only a single patient, one with an HLA-mismatched donor, had failure of primary engraftment; after amendment of the protocol to require HLA matching, there were no additional cases. Just 17% of patients experienced a recurrence of their malignancy by 2 years.

Taken together, the findings suggest that high-dose cyclophosphamide—as combined with two myeloablative conditioning options (to accommodate different malignancies) and with posttransplantation cyclosporine (to reduce the risk of acute GVHD)—may eliminate most of the drawbacks to using mobilized blood cells for transplantation, according to the investigators.

“If these findings are confirmed in future studies, HLA-matched mobilized blood cell transplantation may gain even greater acceptance and further replace marrow as a source of stem cells for most indications,” they maintain.

The patients studied had a median age of 43 years, and slightly more than half were in remission without minimal residual disease.

Blood cells were mobilized with granulocyte colony-stimulating factor (G-CSF). Overall, 28% of patients received grafts from related donors, while 72% received grafts from unrelated donors.

For pretransplant conditioning, patients received fludarabine and targeted busulfan, or total body irradiation with use of a minimum dose of 12 Gy.

The patients were given cyclophosphamide at 50 mg/kg per day on days 3 and 4 after transplantation. This was followed by cyclosporine starting on day 5.

The cumulative 1-year incidence of chronic GVHD as defined by National Institutes of Health criteria (i.e., that requiring systemic immunosuppressive therapy)—the trial’s primary endpoint—was 16%, which fell just short of the goal of 15% the investigators were aiming for (Blood. 2016;127:1502-8). Analyses failed to identify any predictors of this outcome.

Although the estimated cumulative incidence of grade 2 acute GVHD was high, at 77%, none of the patients developed grade 3 or 4 acute GVHD, according to the investigators, who disclosed that they had no competing financial interests.

The single patient who experienced failure of primary engraftment had familial myelodysplastic syndrome and had received a graft from an HLA A-antigen–mismatched unrelated donor.

The 2-year cumulative incidence of nonrelapse mortality was 14%, and the 2-year cumulative incidence of recurrent malignancy was 17%. Projected overall survival was 70%.

Among the 42 patients having at least a year of follow-up, 50% were alive and free of relapse without any systemic immunosuppression at 1 year after transplantation.

High-dose cyclophosphamide is safe and effective when given as prophylaxis for chronic graft-versus-host disease (GVHD) to patients who have undergone transplantation of mobilized blood cells, finds a phase 2 trial reported in Blood.

Investigators led by Dr. Marco Mielcarek, medical director of the Adult Blood and Marrow Transplant Program and an oncologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, enrolled in the trial 43 patients with high-risk hematologic malignancies.

The patients underwent myeloablative conditioning followed by transplantation with growth factor–mobilized blood cells from related or unrelated donors, and were given high-dose cyclophosphamide on two early posttransplantation days.

Main results showed that the cumulative 1-year incidence of chronic GVHD was 16%, less than half of the roughly 35% seen historically with conventional immunosuppression.

Moreover, cyclophosphamide did not appear to compromise engraftment or control of the underlying malignancy. Only a single patient, one with an HLA-mismatched donor, had failure of primary engraftment; after amendment of the protocol to require HLA matching, there were no additional cases. Just 17% of patients experienced a recurrence of their malignancy by 2 years.

Taken together, the findings suggest that high-dose cyclophosphamide—as combined with two myeloablative conditioning options (to accommodate different malignancies) and with posttransplantation cyclosporine (to reduce the risk of acute GVHD)—may eliminate most of the drawbacks to using mobilized blood cells for transplantation, according to the investigators.

“If these findings are confirmed in future studies, HLA-matched mobilized blood cell transplantation may gain even greater acceptance and further replace marrow as a source of stem cells for most indications,” they maintain.

The patients studied had a median age of 43 years, and slightly more than half were in remission without minimal residual disease.

Blood cells were mobilized with granulocyte colony-stimulating factor (G-CSF). Overall, 28% of patients received grafts from related donors, while 72% received grafts from unrelated donors.

For pretransplant conditioning, patients received fludarabine and targeted busulfan, or total body irradiation with use of a minimum dose of 12 Gy.

The patients were given cyclophosphamide at 50 mg/kg per day on days 3 and 4 after transplantation. This was followed by cyclosporine starting on day 5.

The cumulative 1-year incidence of chronic GVHD as defined by National Institutes of Health criteria (i.e., that requiring systemic immunosuppressive therapy)—the trial’s primary endpoint—was 16%, which fell just short of the goal of 15% the investigators were aiming for (Blood. 2016;127:1502-8). Analyses failed to identify any predictors of this outcome.

Although the estimated cumulative incidence of grade 2 acute GVHD was high, at 77%, none of the patients developed grade 3 or 4 acute GVHD, according to the investigators, who disclosed that they had no competing financial interests.

The single patient who experienced failure of primary engraftment had familial myelodysplastic syndrome and had received a graft from an HLA A-antigen–mismatched unrelated donor.

The 2-year cumulative incidence of nonrelapse mortality was 14%, and the 2-year cumulative incidence of recurrent malignancy was 17%. Projected overall survival was 70%.

Among the 42 patients having at least a year of follow-up, 50% were alive and free of relapse without any systemic immunosuppression at 1 year after transplantation.

Prescription medications

Photo courtesy of the CDC

A new study suggests that cost-sharing policies in the US create a barrier to the treatment of chronic myeloid leukemia (CML).

Researchers examined Medicare claims data and found that “Part D” (prescription drug plan) co-insurance policies for “specialty drugs” seem to be reducing or delaying the use of tyrosine kinase inhibitors (TKIs) in patients with CML.

The team reported these findings in the American Journal of Managed Care.

“High out-of-pocket costs for specialty drugs appear to pose a very real barrier to treatment,” said study author Jalpa A. Doshi, PhD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

While there is no standard definition for specialty drugs, the term typically refers to medications requiring special handling, administration, or monitoring. Most are aimed at treating chronic or life-threatening diseases.

Although specialty drugs typically tend to offer significant medical advances over non-specialty drugs, they are correspondingly more expensive. In 2014, such drugs accounted for less than 1% of prescriptions in the US but nearly a third of total prescription spending.

While insurers have been imposing higher cost-sharing requirements as part of their efforts to manage specialty drug spending, there has been limited information about the corresponding impact on patients.

“[I]t was particularly important to examine the extent to which the aggressive cost-sharing policies for specialty drugs seen under Medicare Part D, which are increasingly making their way into the private insurance market, adversely impact access to these treatments even for a condition like cancer,” Dr Doshi said.

So she and her colleagues examined the impact of specialty drug cost-sharing under the Medicare Part D prescription drug benefit on patients with CML. The team analyzed Medicare data on patients who were newly diagnosed with CML to examine whether and how quickly they initiated TKI treatment.

The researchers compared patients who were eligible for low-income subsidies and therefore faced nominal out-of-pocket costs to patients who faced average out-of-pocket costs of $2600 or more for their first 30-day TKI prescription fill.

Results showed that patients in the high-cost group were significantly less likely than the low-cost group to have a Part D claim for a TKI prescription within 6 months of their CML diagnosis. The rates were 45.3% and 66.9%, respectively (P<0.001).

Patients in the high cost-sharing group also took twice as long, on average, to initiate TKI treatment. The mean time to fill a TKI prescription was 50.9 days in the high-cost group and 23.7 days in the low-cost group (P<0.001).

“Medicare Part D was created to increase access to prescription drug treatment among beneficiaries, but our data suggest that current policies are interfering with that goal when it comes to specialty drugs,” Dr Doshi said.

She added that making Part D out-of-pocket costs more consistent and limiting them to more reasonable sums would help mitigate this negative impact.

Dr Doshi and her colleagues are now pursuing further studies of the impact of Part D cost-sharing policies in different disease areas. They hope to gain a better understanding of changes in drug access and of the long-range clinical outcomes and costs associated with any delays or interruptions in treatment.

“We need to know if the current aggressive cost-sharing arrangements have adverse long-term impacts on health and perhaps, paradoxically, increase overall spending due to complications of poorly controlled disease,” Dr Doshi said.

Prescription medications

Photo courtesy of the CDC

A new study suggests that cost-sharing policies in the US create a barrier to the treatment of chronic myeloid leukemia (CML).

Researchers examined Medicare claims data and found that “Part D” (prescription drug plan) co-insurance policies for “specialty drugs” seem to be reducing or delaying the use of tyrosine kinase inhibitors (TKIs) in patients with CML.

The team reported these findings in the American Journal of Managed Care.

“High out-of-pocket costs for specialty drugs appear to pose a very real barrier to treatment,” said study author Jalpa A. Doshi, PhD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

While there is no standard definition for specialty drugs, the term typically refers to medications requiring special handling, administration, or monitoring. Most are aimed at treating chronic or life-threatening diseases.

Although specialty drugs typically tend to offer significant medical advances over non-specialty drugs, they are correspondingly more expensive. In 2014, such drugs accounted for less than 1% of prescriptions in the US but nearly a third of total prescription spending.

While insurers have been imposing higher cost-sharing requirements as part of their efforts to manage specialty drug spending, there has been limited information about the corresponding impact on patients.

“[I]t was particularly important to examine the extent to which the aggressive cost-sharing policies for specialty drugs seen under Medicare Part D, which are increasingly making their way into the private insurance market, adversely impact access to these treatments even for a condition like cancer,” Dr Doshi said.

So she and her colleagues examined the impact of specialty drug cost-sharing under the Medicare Part D prescription drug benefit on patients with CML. The team analyzed Medicare data on patients who were newly diagnosed with CML to examine whether and how quickly they initiated TKI treatment.

The researchers compared patients who were eligible for low-income subsidies and therefore faced nominal out-of-pocket costs to patients who faced average out-of-pocket costs of $2600 or more for their first 30-day TKI prescription fill.

Results showed that patients in the high-cost group were significantly less likely than the low-cost group to have a Part D claim for a TKI prescription within 6 months of their CML diagnosis. The rates were 45.3% and 66.9%, respectively (P<0.001).

Patients in the high cost-sharing group also took twice as long, on average, to initiate TKI treatment. The mean time to fill a TKI prescription was 50.9 days in the high-cost group and 23.7 days in the low-cost group (P<0.001).

“Medicare Part D was created to increase access to prescription drug treatment among beneficiaries, but our data suggest that current policies are interfering with that goal when it comes to specialty drugs,” Dr Doshi said.

She added that making Part D out-of-pocket costs more consistent and limiting them to more reasonable sums would help mitigate this negative impact.

Dr Doshi and her colleagues are now pursuing further studies of the impact of Part D cost-sharing policies in different disease areas. They hope to gain a better understanding of changes in drug access and of the long-range clinical outcomes and costs associated with any delays or interruptions in treatment.

“We need to know if the current aggressive cost-sharing arrangements have adverse long-term impacts on health and perhaps, paradoxically, increase overall spending due to complications of poorly controlled disease,” Dr Doshi said.

Prescription medications

Photo courtesy of the CDC

A new study suggests that cost-sharing policies in the US create a barrier to the treatment of chronic myeloid leukemia (CML).

Researchers examined Medicare claims data and found that “Part D” (prescription drug plan) co-insurance policies for “specialty drugs” seem to be reducing or delaying the use of tyrosine kinase inhibitors (TKIs) in patients with CML.

The team reported these findings in the American Journal of Managed Care.

“High out-of-pocket costs for specialty drugs appear to pose a very real barrier to treatment,” said study author Jalpa A. Doshi, PhD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

While there is no standard definition for specialty drugs, the term typically refers to medications requiring special handling, administration, or monitoring. Most are aimed at treating chronic or life-threatening diseases.

Although specialty drugs typically tend to offer significant medical advances over non-specialty drugs, they are correspondingly more expensive. In 2014, such drugs accounted for less than 1% of prescriptions in the US but nearly a third of total prescription spending.

While insurers have been imposing higher cost-sharing requirements as part of their efforts to manage specialty drug spending, there has been limited information about the corresponding impact on patients.

“[I]t was particularly important to examine the extent to which the aggressive cost-sharing policies for specialty drugs seen under Medicare Part D, which are increasingly making their way into the private insurance market, adversely impact access to these treatments even for a condition like cancer,” Dr Doshi said.

So she and her colleagues examined the impact of specialty drug cost-sharing under the Medicare Part D prescription drug benefit on patients with CML. The team analyzed Medicare data on patients who were newly diagnosed with CML to examine whether and how quickly they initiated TKI treatment.

The researchers compared patients who were eligible for low-income subsidies and therefore faced nominal out-of-pocket costs to patients who faced average out-of-pocket costs of $2600 or more for their first 30-day TKI prescription fill.

Results showed that patients in the high-cost group were significantly less likely than the low-cost group to have a Part D claim for a TKI prescription within 6 months of their CML diagnosis. The rates were 45.3% and 66.9%, respectively (P<0.001).

Patients in the high cost-sharing group also took twice as long, on average, to initiate TKI treatment. The mean time to fill a TKI prescription was 50.9 days in the high-cost group and 23.7 days in the low-cost group (P<0.001).

“Medicare Part D was created to increase access to prescription drug treatment among beneficiaries, but our data suggest that current policies are interfering with that goal when it comes to specialty drugs,” Dr Doshi said.

She added that making Part D out-of-pocket costs more consistent and limiting them to more reasonable sums would help mitigate this negative impact.

Dr Doshi and her colleagues are now pursuing further studies of the impact of Part D cost-sharing policies in different disease areas. They hope to gain a better understanding of changes in drug access and of the long-range clinical outcomes and costs associated with any delays or interruptions in treatment.

“We need to know if the current aggressive cost-sharing arrangements have adverse long-term impacts on health and perhaps, paradoxically, increase overall spending due to complications of poorly controlled disease,” Dr Doshi said.

Dr. Kalaycio: I'm starting with the less controversial questions to begin with. I think the next set have the potential for some more controversy. Before we leave the initial assessment of CML, do either of you have observations regarding referrals that you get about which you would like to either dispel myths or remind practitioners about best practices in patients newly diagnosed with CML?

I think, moving forward it would be really important to have documentation of concomitant risk factors such as smoking and so on that are essentially driving outcomes more than the TKI treatment or the CML itself. – Michael Deininger, MD, PhDDr. Mauro: I can mention one thing. I think when thinking about initial molecular diagnostic results, it is important to point out that testing should screen broadly for different fusions, namely P190 and P210, or variant (p230) transcripts. There are rare patients in chronic phase with non-p210 fusion who need to be followed with specific PCR. On this same topic, the measurement of transcripts at presentation (ie, before treatment) has become quite important and whereas formerly had not been emphasized, presently all patients should have ”baseline” transcript levels.

Dr. Deininger: I think one issue that comes up once in a while is that spleen measurements are done by ultrasound. Technically it's more accurate, but all the clinical risk scores and the prognostication is based on the old fashioned—but probably highly inaccurate—technology of palpation. This is what counts, this is the value to document. I think, moving forward it would be really important to have documentation of concomitant risk factors such as smoking and so on that are essentially driving outcomes more than the TKI treatment or the CML itself. Getting a good handle of those risk factors at diagnosis is also important.

Dr. Kalaycio: I think that's a very important point. That's where I was going to go next with this conversation. I was going to avoid the conversation about which TKI to choose as initial treatment. I think that's a debate unto itself.

I would like to ask you how you might assess cardiovascular risk before placing a patient on nilotinib. You got to that a little bit, Dr. Deininger. Could you expand on what else you might review as far as whether or not you feel a patient is a good candidate to start on nilotinib?

Dr. Deininger: Specifically, with regard to nilotinib, we would always get a baseline electrocardiogram. We would do a clinical exam. We would not do an echocardiogram just routinely in the absence of a cardiovascular history or any clinical evidence for heart failure or other cardiovascular issues.

We've adopted the practice of doing a lipid panel. Of course we would include fasting glucose as well. Some of these recommendations are probably somewhat on the soft side, because it's not yet clear what to do with the information.

On the other hand, I think for a patient who is being considered for nilotinib one wants to make sure that one really does the best to minimize the cardiovascular risk factors. Of course that would include smoking history and taking blood pressure and making sure that these risk factors are controlled.

If people have a presentation that is really out of whack in terms of their risk factor management, I would send them to an internist or even a cardiologist to help me optimize the cardiovascular prevention strategy.

Dr. Kalaycio: Great. Similarly, Dr. Mauro, how do you assess pulmonary risk before placing a patient on dasatinib?

Dr. Mauro: I think here we are focused on the less frequent and also less well understood potential toxicity of pulmonary hypertension, coupled with the more common risk of pleural and pericardial effusions.

I'm not sure how much we've learned in clinical studies looking at baseline chest X-rays or timing of X-rays during treatment. I think our best tool in the prevention and management of pleural and pericardial effusions is full discussion with patients about risk and what to look for, attention to any and all symptoms, and appropriate deployment of diagnostics as indicated.

It's interesting to consider whether baseline echocardiography for measurement of pulmonary pressures is warranted. I would say now we're on probably somewhat softer ground, first because on routine echocardiogram pulmonary pressure can't be measured readily unless there is some valvular regurgitation. As well, it is stated that pulmonary hypertension is only properly diagnosed by right heart catheterization. While I'm tempted to do routine echocardiogram studies, I think that such a recommendation still may be perhaps the realm of a clinical study. We need to explore that further. I think with dasatinib there may be certain patients at higher risk, although the data are somewhat limited. There seem to be certain conditions potentially associated with more pleural and pericardial toxicity, including cardiovascular disease and autoimmune disease. There may be circumstances during treatment—lymphocytosis, for example—that may be associated with greater risk. I think expectant management may still be the right approach and echocardiography and more aggressive diagnostics be reserved for patients in whom there might be much more clinical consequence.

Dr. Kalaycio: I'd like to pursue that a little bit further because sometimes the patients will come to us having already had an echocardiogram that may actually show some mild pulmonary hypertension and maybe they've got significant cardiovascular risk factors where you would otherwise be thinking about using dasatinib. Here's someone with pulmonary hypertension, at least by echocardiographic criteria, would that be enough to dissuade you from the use of dasatinib?

Dr. Mauro: I think it would certainly require significant consideration, understanding what the basis of the pulmonary hypertension is for that patient, and risk with adding dasatinib. I think the good news is the low incidence and the reversibility for the most part of dasatinib-associated pulmonary hypertension.

Again, I think the mechanism of action and the pathophysiology isn't completely understood, although there is the intriguing notion that imatinib has been reported to potentially mitigate pulmonary hypertension whereas dasatinib triggers it—a ”closed loop” if you will and an area ripe for research.

I would probably think that a patient with preexisting pulmonary hypertension in the new diagnosis setting might be the kind of patient for whom you really might weigh the pluses versus the minuses of a second generation TKI versus imatinib.

E-mail: [email protected]

Dr. Kalaycio: I'm starting with the less controversial questions to begin with. I think the next set have the potential for some more controversy. Before we leave the initial assessment of CML, do either of you have observations regarding referrals that you get about which you would like to either dispel myths or remind practitioners about best practices in patients newly diagnosed with CML?

I think, moving forward it would be really important to have documentation of concomitant risk factors such as smoking and so on that are essentially driving outcomes more than the TKI treatment or the CML itself. – Michael Deininger, MD, PhDDr. Mauro: I can mention one thing. I think when thinking about initial molecular diagnostic results, it is important to point out that testing should screen broadly for different fusions, namely P190 and P210, or variant (p230) transcripts. There are rare patients in chronic phase with non-p210 fusion who need to be followed with specific PCR. On this same topic, the measurement of transcripts at presentation (ie, before treatment) has become quite important and whereas formerly had not been emphasized, presently all patients should have ”baseline” transcript levels.

Dr. Deininger: I think one issue that comes up once in a while is that spleen measurements are done by ultrasound. Technically it's more accurate, but all the clinical risk scores and the prognostication is based on the old fashioned—but probably highly inaccurate—technology of palpation. This is what counts, this is the value to document. I think, moving forward it would be really important to have documentation of concomitant risk factors such as smoking and so on that are essentially driving outcomes more than the TKI treatment or the CML itself. Getting a good handle of those risk factors at diagnosis is also important.

Dr. Kalaycio: I think that's a very important point. That's where I was going to go next with this conversation. I was going to avoid the conversation about which TKI to choose as initial treatment. I think that's a debate unto itself.

I would like to ask you how you might assess cardiovascular risk before placing a patient on nilotinib. You got to that a little bit, Dr. Deininger. Could you expand on what else you might review as far as whether or not you feel a patient is a good candidate to start on nilotinib?

Dr. Deininger: Specifically, with regard to nilotinib, we would always get a baseline electrocardiogram. We would do a clinical exam. We would not do an echocardiogram just routinely in the absence of a cardiovascular history or any clinical evidence for heart failure or other cardiovascular issues.

We've adopted the practice of doing a lipid panel. Of course we would include fasting glucose as well. Some of these recommendations are probably somewhat on the soft side, because it's not yet clear what to do with the information.

On the other hand, I think for a patient who is being considered for nilotinib one wants to make sure that one really does the best to minimize the cardiovascular risk factors. Of course that would include smoking history and taking blood pressure and making sure that these risk factors are controlled.

If people have a presentation that is really out of whack in terms of their risk factor management, I would send them to an internist or even a cardiologist to help me optimize the cardiovascular prevention strategy.

Dr. Kalaycio: Great. Similarly, Dr. Mauro, how do you assess pulmonary risk before placing a patient on dasatinib?

Dr. Mauro: I think here we are focused on the less frequent and also less well understood potential toxicity of pulmonary hypertension, coupled with the more common risk of pleural and pericardial effusions.

I'm not sure how much we've learned in clinical studies looking at baseline chest X-rays or timing of X-rays during treatment. I think our best tool in the prevention and management of pleural and pericardial effusions is full discussion with patients about risk and what to look for, attention to any and all symptoms, and appropriate deployment of diagnostics as indicated.

It's interesting to consider whether baseline echocardiography for measurement of pulmonary pressures is warranted. I would say now we're on probably somewhat softer ground, first because on routine echocardiogram pulmonary pressure can't be measured readily unless there is some valvular regurgitation. As well, it is stated that pulmonary hypertension is only properly diagnosed by right heart catheterization. While I'm tempted to do routine echocardiogram studies, I think that such a recommendation still may be perhaps the realm of a clinical study. We need to explore that further. I think with dasatinib there may be certain patients at higher risk, although the data are somewhat limited. There seem to be certain conditions potentially associated with more pleural and pericardial toxicity, including cardiovascular disease and autoimmune disease. There may be circumstances during treatment—lymphocytosis, for example—that may be associated with greater risk. I think expectant management may still be the right approach and echocardiography and more aggressive diagnostics be reserved for patients in whom there might be much more clinical consequence.

Dr. Kalaycio: I'd like to pursue that a little bit further because sometimes the patients will come to us having already had an echocardiogram that may actually show some mild pulmonary hypertension and maybe they've got significant cardiovascular risk factors where you would otherwise be thinking about using dasatinib. Here's someone with pulmonary hypertension, at least by echocardiographic criteria, would that be enough to dissuade you from the use of dasatinib?

Dr. Mauro: I think it would certainly require significant consideration, understanding what the basis of the pulmonary hypertension is for that patient, and risk with adding dasatinib. I think the good news is the low incidence and the reversibility for the most part of dasatinib-associated pulmonary hypertension.

Again, I think the mechanism of action and the pathophysiology isn't completely understood, although there is the intriguing notion that imatinib has been reported to potentially mitigate pulmonary hypertension whereas dasatinib triggers it—a ”closed loop” if you will and an area ripe for research.

I would probably think that a patient with preexisting pulmonary hypertension in the new diagnosis setting might be the kind of patient for whom you really might weigh the pluses versus the minuses of a second generation TKI versus imatinib.

E-mail: [email protected]

Dr. Kalaycio: I'm starting with the less controversial questions to begin with. I think the next set have the potential for some more controversy. Before we leave the initial assessment of CML, do either of you have observations regarding referrals that you get about which you would like to either dispel myths or remind practitioners about best practices in patients newly diagnosed with CML?

I think, moving forward it would be really important to have documentation of concomitant risk factors such as smoking and so on that are essentially driving outcomes more than the TKI treatment or the CML itself. – Michael Deininger, MD, PhDDr. Mauro: I can mention one thing. I think when thinking about initial molecular diagnostic results, it is important to point out that testing should screen broadly for different fusions, namely P190 and P210, or variant (p230) transcripts. There are rare patients in chronic phase with non-p210 fusion who need to be followed with specific PCR. On this same topic, the measurement of transcripts at presentation (ie, before treatment) has become quite important and whereas formerly had not been emphasized, presently all patients should have ”baseline” transcript levels.

Dr. Deininger: I think one issue that comes up once in a while is that spleen measurements are done by ultrasound. Technically it's more accurate, but all the clinical risk scores and the prognostication is based on the old fashioned—but probably highly inaccurate—technology of palpation. This is what counts, this is the value to document. I think, moving forward it would be really important to have documentation of concomitant risk factors such as smoking and so on that are essentially driving outcomes more than the TKI treatment or the CML itself. Getting a good handle of those risk factors at diagnosis is also important.

Dr. Kalaycio: I think that's a very important point. That's where I was going to go next with this conversation. I was going to avoid the conversation about which TKI to choose as initial treatment. I think that's a debate unto itself.

I would like to ask you how you might assess cardiovascular risk before placing a patient on nilotinib. You got to that a little bit, Dr. Deininger. Could you expand on what else you might review as far as whether or not you feel a patient is a good candidate to start on nilotinib?

Dr. Deininger: Specifically, with regard to nilotinib, we would always get a baseline electrocardiogram. We would do a clinical exam. We would not do an echocardiogram just routinely in the absence of a cardiovascular history or any clinical evidence for heart failure or other cardiovascular issues.

We've adopted the practice of doing a lipid panel. Of course we would include fasting glucose as well. Some of these recommendations are probably somewhat on the soft side, because it's not yet clear what to do with the information.

On the other hand, I think for a patient who is being considered for nilotinib one wants to make sure that one really does the best to minimize the cardiovascular risk factors. Of course that would include smoking history and taking blood pressure and making sure that these risk factors are controlled.

If people have a presentation that is really out of whack in terms of their risk factor management, I would send them to an internist or even a cardiologist to help me optimize the cardiovascular prevention strategy.

Dr. Kalaycio: Great. Similarly, Dr. Mauro, how do you assess pulmonary risk before placing a patient on dasatinib?

Dr. Mauro: I think here we are focused on the less frequent and also less well understood potential toxicity of pulmonary hypertension, coupled with the more common risk of pleural and pericardial effusions.

I'm not sure how much we've learned in clinical studies looking at baseline chest X-rays or timing of X-rays during treatment. I think our best tool in the prevention and management of pleural and pericardial effusions is full discussion with patients about risk and what to look for, attention to any and all symptoms, and appropriate deployment of diagnostics as indicated.

It's interesting to consider whether baseline echocardiography for measurement of pulmonary pressures is warranted. I would say now we're on probably somewhat softer ground, first because on routine echocardiogram pulmonary pressure can't be measured readily unless there is some valvular regurgitation. As well, it is stated that pulmonary hypertension is only properly diagnosed by right heart catheterization. While I'm tempted to do routine echocardiogram studies, I think that such a recommendation still may be perhaps the realm of a clinical study. We need to explore that further. I think with dasatinib there may be certain patients at higher risk, although the data are somewhat limited. There seem to be certain conditions potentially associated with more pleural and pericardial toxicity, including cardiovascular disease and autoimmune disease. There may be circumstances during treatment—lymphocytosis, for example—that may be associated with greater risk. I think expectant management may still be the right approach and echocardiography and more aggressive diagnostics be reserved for patients in whom there might be much more clinical consequence.

Dr. Kalaycio: I'd like to pursue that a little bit further because sometimes the patients will come to us having already had an echocardiogram that may actually show some mild pulmonary hypertension and maybe they've got significant cardiovascular risk factors where you would otherwise be thinking about using dasatinib. Here's someone with pulmonary hypertension, at least by echocardiographic criteria, would that be enough to dissuade you from the use of dasatinib?

Dr. Mauro: I think it would certainly require significant consideration, understanding what the basis of the pulmonary hypertension is for that patient, and risk with adding dasatinib. I think the good news is the low incidence and the reversibility for the most part of dasatinib-associated pulmonary hypertension.

Again, I think the mechanism of action and the pathophysiology isn't completely understood, although there is the intriguing notion that imatinib has been reported to potentially mitigate pulmonary hypertension whereas dasatinib triggers it—a ”closed loop” if you will and an area ripe for research.

I would probably think that a patient with preexisting pulmonary hypertension in the new diagnosis setting might be the kind of patient for whom you really might weigh the pluses versus the minuses of a second generation TKI versus imatinib.

E-mail: [email protected]

Prescription medications

Photo courtesy of the CDC

New research suggests that starting all patients with chronic myeloid leukemia (CML) on the generic form of Gleevec, imatinib, could result in substantial savings for patients and insurance companies in the US.

Researchers found that starting treatment with generic imatinib and then switching patients to the second-generation tyrosine kinase inhibitors (TKIs) dasatinib (Sprycel) and nilotinib (Tasigna) if necessary would be more cost-effective than the current standard of care, which allows physicians to start patients on any of the aforementioned TKIs.

In fact, the data suggest that starting all CML patients on generic imatinib could reduce the cost of treatment per patient over 5 years by nearly $90,000.

“If we start all patients on the generic form of Gleevec, and it works, then they are on a generic for the rest of their lives,” said study author William V. Padula, PhD, of Johns Hopkins University in Baltimore, Maryland.

“This amounts to a huge cost savings for them and their insurers.”

Dr Padula and his colleagues described these potential savings in the Journal of the National Cancer Institute.

The researchers compared the cost-effectiveness of the different TKIs by analyzing Truven Health Analytics MarketScan data from newly diagnosed CML patients between January 1, 2011, and December 31, 2012.

The team constructed Markov models to compare the 5-year cost-effectiveness of imatinib-first vs physician’s choice. The main outcome of the models was cost per quality-adjusted life-year (QALY).

The researchers interpreted outcomes based on a willingness-to-pay threshold of $100,000/QALY. They found that both imatinib-first and physician’s choice met that threshold.

However, imatinib-first cost less over 5 years and conferred only slightly fewer QALYs than physician’s choice—$277,401 and 3.87 QALYs for imatinib-first and $365,744 and 3.97 QALYs for physician’s choice.

So that’s a 0.10 decrement in QALYs and a savings of $88,343 over 5 years with imatinib-first. The imatinib-first incremental cost-effectiveness ratio was about $883,730/QALY.

“There is minimal risk to starting all patients on imatinib first,” Dr Padula said. “If the patient can’t tolerate the medication or it seems to be ineffective in that patient, then we can switch the patient to a more expensive drug.”

“Insurance companies have the ability to dictate which drugs physicians prescribe first, and they regularly do. Doing so here would mean very little risk to health and a lot of cost savings.”

Prescription medications

Photo courtesy of the CDC

New research suggests that starting all patients with chronic myeloid leukemia (CML) on the generic form of Gleevec, imatinib, could result in substantial savings for patients and insurance companies in the US.

Researchers found that starting treatment with generic imatinib and then switching patients to the second-generation tyrosine kinase inhibitors (TKIs) dasatinib (Sprycel) and nilotinib (Tasigna) if necessary would be more cost-effective than the current standard of care, which allows physicians to start patients on any of the aforementioned TKIs.

In fact, the data suggest that starting all CML patients on generic imatinib could reduce the cost of treatment per patient over 5 years by nearly $90,000.

“If we start all patients on the generic form of Gleevec, and it works, then they are on a generic for the rest of their lives,” said study author William V. Padula, PhD, of Johns Hopkins University in Baltimore, Maryland.

“This amounts to a huge cost savings for them and their insurers.”

Dr Padula and his colleagues described these potential savings in the Journal of the National Cancer Institute.

The researchers compared the cost-effectiveness of the different TKIs by analyzing Truven Health Analytics MarketScan data from newly diagnosed CML patients between January 1, 2011, and December 31, 2012.

The team constructed Markov models to compare the 5-year cost-effectiveness of imatinib-first vs physician’s choice. The main outcome of the models was cost per quality-adjusted life-year (QALY).

The researchers interpreted outcomes based on a willingness-to-pay threshold of $100,000/QALY. They found that both imatinib-first and physician’s choice met that threshold.

However, imatinib-first cost less over 5 years and conferred only slightly fewer QALYs than physician’s choice—$277,401 and 3.87 QALYs for imatinib-first and $365,744 and 3.97 QALYs for physician’s choice.

So that’s a 0.10 decrement in QALYs and a savings of $88,343 over 5 years with imatinib-first. The imatinib-first incremental cost-effectiveness ratio was about $883,730/QALY.

“There is minimal risk to starting all patients on imatinib first,” Dr Padula said. “If the patient can’t tolerate the medication or it seems to be ineffective in that patient, then we can switch the patient to a more expensive drug.”

“Insurance companies have the ability to dictate which drugs physicians prescribe first, and they regularly do. Doing so here would mean very little risk to health and a lot of cost savings.”

Prescription medications

Photo courtesy of the CDC

New research suggests that starting all patients with chronic myeloid leukemia (CML) on the generic form of Gleevec, imatinib, could result in substantial savings for patients and insurance companies in the US.

Researchers found that starting treatment with generic imatinib and then switching patients to the second-generation tyrosine kinase inhibitors (TKIs) dasatinib (Sprycel) and nilotinib (Tasigna) if necessary would be more cost-effective than the current standard of care, which allows physicians to start patients on any of the aforementioned TKIs.

In fact, the data suggest that starting all CML patients on generic imatinib could reduce the cost of treatment per patient over 5 years by nearly $90,000.

“If we start all patients on the generic form of Gleevec, and it works, then they are on a generic for the rest of their lives,” said study author William V. Padula, PhD, of Johns Hopkins University in Baltimore, Maryland.

“This amounts to a huge cost savings for them and their insurers.”

Dr Padula and his colleagues described these potential savings in the Journal of the National Cancer Institute.

The researchers compared the cost-effectiveness of the different TKIs by analyzing Truven Health Analytics MarketScan data from newly diagnosed CML patients between January 1, 2011, and December 31, 2012.

The team constructed Markov models to compare the 5-year cost-effectiveness of imatinib-first vs physician’s choice. The main outcome of the models was cost per quality-adjusted life-year (QALY).

The researchers interpreted outcomes based on a willingness-to-pay threshold of $100,000/QALY. They found that both imatinib-first and physician’s choice met that threshold.

However, imatinib-first cost less over 5 years and conferred only slightly fewer QALYs than physician’s choice—$277,401 and 3.87 QALYs for imatinib-first and $365,744 and 3.97 QALYs for physician’s choice.

So that’s a 0.10 decrement in QALYs and a savings of $88,343 over 5 years with imatinib-first. The imatinib-first incremental cost-effectiveness ratio was about $883,730/QALY.

“There is minimal risk to starting all patients on imatinib first,” Dr Padula said. “If the patient can’t tolerate the medication or it seems to be ineffective in that patient, then we can switch the patient to a more expensive drug.”

“Insurance companies have the ability to dictate which drugs physicians prescribe first, and they regularly do. Doing so here would mean very little risk to health and a lot of cost savings.”

 

 

Three generations of a family

 

A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.

Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.

“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.

“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”

To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.

In all, 9 of the families (3%) had germline DDX41 mutations.

Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.

One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.

Five families carried novel DDX41 mutations.

One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.

Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.

One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.

And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.

“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.

“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”

 

 

Three generations of a family

 

A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.

Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.

“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.

“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”

To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.

In all, 9 of the families (3%) had germline DDX41 mutations.

Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.

One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.

Five families carried novel DDX41 mutations.

One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.

Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.

One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.

And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.

“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.

“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”

 

 

Three generations of a family

 

A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.

Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.

“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.

“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”

To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.

In all, 9 of the families (3%) had germline DDX41 mutations.

Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.

One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.

Five families carried novel DDX41 mutations.

One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.

Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.

One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.

And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.

“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.

“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”

In heavily pretreated patients with chronic phase chronic myeloid leukemia (CP-CML), response to the tyrosine kinase inhibitor ponatinib did not depend on baseline mutation status, and no single or compound mutation was a major driver of primary or secondary resistance to ponatinib, according to researchers.

Irrespective of baseline mutation status, responses to ponatinib were durable. As determined by next-generation sequencing (NGS), patients with zero, one, or two or more BCR-ABL1 mutations had rates of 50%-61% for major cytogenetic response (MCyR) by 1 year and 29%-45% for major molecular response (MMR) at any time. The rates were similar to those observed with mutation status determined by Sanger sequencing. Rates of sustained response at 2 years for MCyR and MMR were 87% and 65%, respectively (Blood. 2016 Feb 11. doi: 10.1182/blood-2015-08-660977).

Difu Wu/CC BY-SA 3.0

Sanger sequencing typically is used to identify BCR-ABL1 mutations associated with tyrosine kinase inhibitor (TKI) resistance, but the method fails to detect low-level mutations that occur in less than 10%-20% of cells. Researchers used NGS to determine the impact of low-level mutations, as well as compound mutations, on the efficacy of the third generation TKI ponatinib.

Ponatinib is the most potent BCR-ABL1 TKI but is associated with considerable cardiovascular toxicity.

“The role of NGS in this setting may be to identify patients with (low level) T315I who are unlikely to derive lasting benefit from second-generation TKIs, but have a high likelihood of achieving durable cytogenetic and molecular responses to ponatinib, an important factor for balancing risks and benefits of salvage therapy selection,” wrote Dr. Michael W. Deininger, Chief of Hematology at the Huntsman Cancer Institute at the University of Utah, Salt Lake City, and his colleagues.

Patients with low-level mutations had similar response rates to those with no mutations: MCyR by one year and MMR at any time were 43% and 31%, respectively, compared with 50% and 29%. Response rates were higher in patients with compound mutations (64% and 52%) or one or more mutation (57% and 64%). The researchers speculated that the lower response rates in patients with low level or no mutations may reflect resistance mechanisms independent of BCR-ABL1.

Analysis of postbaseline samples from 127 patients (24 of whom had discontinued ponatinib for at least 1 month) determined the impact of acquired resistance. At a median follow-up of 30.1 months, emergence of previously undetected single and compound mutants during ponatinib therapy was observed in 8 patients.

The study analyzed patients from the PACE trial who had CP-CML with resistance or intolerance to dasatinib or nilotinib, or with a T315I mutation, and who were treated with ponatinib. All 267 patients had baseline mutation status determined by Sanger sequencing, with 161 mutations detected in 131 patients. NGS identified these and 105 additional mutations. Consistent with greater sensitivity of NGS, the proportion of patients with no baseline mutations by 39% by NGS vs. 51% by Sanger sequencing, and the proportion with multiple mutations was 23% vs. 10%.

The study was funded by ARIAD Pharmaceuticals. Dr. Deininger reported financial ties to ARIAD, Bristol Myers-Squibb, Novartis, Celgene, Genzyme, Gilead, Incyte, and Pfizer. Several of his coauthors reported ties to industry.

In heavily pretreated patients with chronic phase chronic myeloid leukemia (CP-CML), response to the tyrosine kinase inhibitor ponatinib did not depend on baseline mutation status, and no single or compound mutation was a major driver of primary or secondary resistance to ponatinib, according to researchers.

Irrespective of baseline mutation status, responses to ponatinib were durable. As determined by next-generation sequencing (NGS), patients with zero, one, or two or more BCR-ABL1 mutations had rates of 50%-61% for major cytogenetic response (MCyR) by 1 year and 29%-45% for major molecular response (MMR) at any time. The rates were similar to those observed with mutation status determined by Sanger sequencing. Rates of sustained response at 2 years for MCyR and MMR were 87% and 65%, respectively (Blood. 2016 Feb 11. doi: 10.1182/blood-2015-08-660977).

Difu Wu/CC BY-SA 3.0

Sanger sequencing typically is used to identify BCR-ABL1 mutations associated with tyrosine kinase inhibitor (TKI) resistance, but the method fails to detect low-level mutations that occur in less than 10%-20% of cells. Researchers used NGS to determine the impact of low-level mutations, as well as compound mutations, on the efficacy of the third generation TKI ponatinib.

Ponatinib is the most potent BCR-ABL1 TKI but is associated with considerable cardiovascular toxicity.

“The role of NGS in this setting may be to identify patients with (low level) T315I who are unlikely to derive lasting benefit from second-generation TKIs, but have a high likelihood of achieving durable cytogenetic and molecular responses to ponatinib, an important factor for balancing risks and benefits of salvage therapy selection,” wrote Dr. Michael W. Deininger, Chief of Hematology at the Huntsman Cancer Institute at the University of Utah, Salt Lake City, and his colleagues.

Patients with low-level mutations had similar response rates to those with no mutations: MCyR by one year and MMR at any time were 43% and 31%, respectively, compared with 50% and 29%. Response rates were higher in patients with compound mutations (64% and 52%) or one or more mutation (57% and 64%). The researchers speculated that the lower response rates in patients with low level or no mutations may reflect resistance mechanisms independent of BCR-ABL1.

Analysis of postbaseline samples from 127 patients (24 of whom had discontinued ponatinib for at least 1 month) determined the impact of acquired resistance. At a median follow-up of 30.1 months, emergence of previously undetected single and compound mutants during ponatinib therapy was observed in 8 patients.

The study analyzed patients from the PACE trial who had CP-CML with resistance or intolerance to dasatinib or nilotinib, or with a T315I mutation, and who were treated with ponatinib. All 267 patients had baseline mutation status determined by Sanger sequencing, with 161 mutations detected in 131 patients. NGS identified these and 105 additional mutations. Consistent with greater sensitivity of NGS, the proportion of patients with no baseline mutations by 39% by NGS vs. 51% by Sanger sequencing, and the proportion with multiple mutations was 23% vs. 10%.

The study was funded by ARIAD Pharmaceuticals. Dr. Deininger reported financial ties to ARIAD, Bristol Myers-Squibb, Novartis, Celgene, Genzyme, Gilead, Incyte, and Pfizer. Several of his coauthors reported ties to industry.

In heavily pretreated patients with chronic phase chronic myeloid leukemia (CP-CML), response to the tyrosine kinase inhibitor ponatinib did not depend on baseline mutation status, and no single or compound mutation was a major driver of primary or secondary resistance to ponatinib, according to researchers.

Irrespective of baseline mutation status, responses to ponatinib were durable. As determined by next-generation sequencing (NGS), patients with zero, one, or two or more BCR-ABL1 mutations had rates of 50%-61% for major cytogenetic response (MCyR) by 1 year and 29%-45% for major molecular response (MMR) at any time. The rates were similar to those observed with mutation status determined by Sanger sequencing. Rates of sustained response at 2 years for MCyR and MMR were 87% and 65%, respectively (Blood. 2016 Feb 11. doi: 10.1182/blood-2015-08-660977).

Difu Wu/CC BY-SA 3.0

Sanger sequencing typically is used to identify BCR-ABL1 mutations associated with tyrosine kinase inhibitor (TKI) resistance, but the method fails to detect low-level mutations that occur in less than 10%-20% of cells. Researchers used NGS to determine the impact of low-level mutations, as well as compound mutations, on the efficacy of the third generation TKI ponatinib.

Ponatinib is the most potent BCR-ABL1 TKI but is associated with considerable cardiovascular toxicity.

“The role of NGS in this setting may be to identify patients with (low level) T315I who are unlikely to derive lasting benefit from second-generation TKIs, but have a high likelihood of achieving durable cytogenetic and molecular responses to ponatinib, an important factor for balancing risks and benefits of salvage therapy selection,” wrote Dr. Michael W. Deininger, Chief of Hematology at the Huntsman Cancer Institute at the University of Utah, Salt Lake City, and his colleagues.

Patients with low-level mutations had similar response rates to those with no mutations: MCyR by one year and MMR at any time were 43% and 31%, respectively, compared with 50% and 29%. Response rates were higher in patients with compound mutations (64% and 52%) or one or more mutation (57% and 64%). The researchers speculated that the lower response rates in patients with low level or no mutations may reflect resistance mechanisms independent of BCR-ABL1.

Analysis of postbaseline samples from 127 patients (24 of whom had discontinued ponatinib for at least 1 month) determined the impact of acquired resistance. At a median follow-up of 30.1 months, emergence of previously undetected single and compound mutants during ponatinib therapy was observed in 8 patients.

The study analyzed patients from the PACE trial who had CP-CML with resistance or intolerance to dasatinib or nilotinib, or with a T315I mutation, and who were treated with ponatinib. All 267 patients had baseline mutation status determined by Sanger sequencing, with 161 mutations detected in 131 patients. NGS identified these and 105 additional mutations. Consistent with greater sensitivity of NGS, the proportion of patients with no baseline mutations by 39% by NGS vs. 51% by Sanger sequencing, and the proportion with multiple mutations was 23% vs. 10%.

The study was funded by ARIAD Pharmaceuticals. Dr. Deininger reported financial ties to ARIAD, Bristol Myers-Squibb, Novartis, Celgene, Genzyme, Gilead, Incyte, and Pfizer. Several of his coauthors reported ties to industry.

CML cells

Image by Difu Wu

Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.

Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.

The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.

“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.

“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”

Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.

In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.

Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.

When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.

When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.

The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.

The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.

Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.

The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.

The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.

The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.

Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.

The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.

Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.

The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.

CML cells

Image by Difu Wu

Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.

Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.

The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.

“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.

“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”

Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.

In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.

Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.

When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.

When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.

The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.

The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.

Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.

The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.

The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.

The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.

Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.

The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.

Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.

The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.

CML cells

Image by Difu Wu

Preclinical research suggests chronic myeloid leukemia (CML) patients have a heterogeneous population of long-term hematopoietic stem cells (LTHSCs)—some that can initiate leukemia and some that cannot.

Researchers found they could identify the leukemia-initiating cells by measuring expression of the thrombopoietin receptor MPL. Cells with high MPL expression could initiate CML in mice.

The team said these results suggest the leukemic LTHSCs are the cells responsible for relapse in CML.

“This shows that not all leukemia stem cells are equal,” said study author Ravi Bhatia, MD, of the University of Alabama Birmingham.

“Some are more prone to causing leukemia and relapses, while some others may just hang around without potential for contributing to relapse.”

Dr Bhatia and his colleagues reported these findings in The Journal of Clinical Investigation.

In their experiments, the team used an inducible transgenic mouse model of CML, where the BCR-ABL gene fusion is under the control of a tetracycline-regulated enhancer. This model creates a chronic myeloproliferative disorder that resembles chronic phase CML.

Previous work had shown that only cells with an LTHSC phenotype were capable of long-term repopulation and leukemia-initiating capacity after transplantation to another mouse.

When the researchers transplanted LTHSCs from CML-model mice to other mice, 11 of 20 recipients developed CML, and 9 of 20 showed engraftment with CML cells but did not develop the leukocytosis characteristic of leukemia.

When the LTHSCs from the primary-recipient mice were transferred to secondary recipients, 7 of 17 mice receiving cells from leukemic mice developed CML, and none of the secondary-recipient mice receiving cells from the non-leukemic mice developed CML.

The researchers tested these 2 groups of LTHSCs for differences in gene expression. They found significant differences between the leukemic and non-leukemic LTHSCs for the genes Mpl, c-Myc, CD47, Pten, Sirt1, Ptch1, and Tie2.

The team then decided to focus on Mpl. They used flow cytometry to select LTHSCs with either high or low Mpl expression from CML-model BCR-ABL mice.

Seven of 16 mice receiving Mpl-Hi LTHSCs developed leukemia after transplantation, compared with 1 of 17 receiving Mpl-Lo LTHSCs. This suggested an increased leukemogenic capacity for the Mpl-Hi LTHSCs.

The researchers also investigated the impact of cell-cycle status. They found that CML Mpl-Hi LTHSCs that were in a resting stage of the cell cycle had enhanced long-term engraftment and leukemogenic capacity compared with cycling Mpl-Hi LTHSCs.

The team used virus vectors and shRNA to create Mpl knockdown BCR-ABL LTHSCs and showed that the knockdown cells had a greatly reduced ability to produce leukemia in recipient mice.

The Mpl knockdown cells, after stimulation by the Mpl ligand thrombopoietin, also had reduced expression of the activated transcription factors p-STAT3 and p-STAT5, compared with controls.

Finally, the researchers examined human CML cells for differences between MPL-Hi LTHSCs and MPL-Lo LTHSCs. The results were similar to those observed in mice.

The human MPL-Hi LTHSCs had a higher rate of engraftment than the human MPL-Lo LTHSCs, as tested in a xenograft model using immunodeficient mice.

Additionally, the human MPL-Hi LTHSCs had reduced sensitivity to nilotinib compared with MPL-Lo LTHSCs. However, a Jak/STAT inhibitor significantly reduced cell growth and increased apoptosis in human MPL-Hi LTHSCs.

The researchers concluded that MPL expression is a marker and key regulator of leukemogenic potential and drug sensitivity of CML LTHSCs. They said their findings support further investigation of approaches to antagonize MPL signaling as a potential therapeutic strategy to eliminate leukemia-initiating LTHSCs.