CML

 

 

HSCT preparation

Photo by Chad McNeeley

 

SAN DIEGO—Researchers believe they have identified patients with chronic myeloid leukemia (CML) who are likely to derive long-term benefit from allogeneic hematopoietic stem cell transplant (allo-HSCT).

The researchers found that CML patients have a low risk of long-term morbidity if they undergo HSCT before the age of 45, are conditioned with busulfan and cyclophosphamide (Bu/Cy), and receive a graft from a matched, related donor (MRD).

Jessica Wu, of the University of Alabama at Birmingham, presented these findings at the 2016 ASH Annual Meeting (abstract 823*).

Wu noted that allogeneic HSCT is potentially curative for CML, but this method of treatment has been on the decline since the introduction of tyrosine kinase inhibitors (TKIs). And today, few CML patients undergo allo-HSCT.

She said that although TKIs can induce remission in CML patients, the drugs also fail to eradicate leukemia, can produce side effects that impact patients’ quality of life, and come with a significant financial burden (estimated at $92,000 to $138,000 per patient per year).

With this in mind, Wu and her colleagues set out to determine if certain CML patients might benefit from allo-HSCT long-term. The team also wanted to quantify overall and cause-specific late mortality after allo-HSCT and the long-term burden of severe/life-threatening chronic health conditions after allo-HSCT.

Patient population

The researchers studied 637 CML patients treated with allo-HSCT between 1981 and 2010 at City of Hope in Duarte, California, or the University of Minnesota in Minneapolis/Saint Paul. The patients had to have survived at least 2 years post-transplant.

About 60% of patients were male, and 67% were non-Hispanic white. Their median age at HSCT was 36.4 years, and 65% received an MRD graft. Nineteen percent of patients were transplanted in 1980-1989, 52% were transplanted in 1990-1999, and 29% were transplanted in 2000-2010.

Fifty-eight percent of patients received Cy/total body irradiation (TBI), 18% received Bu/Cy, and 3% received reduced-intensity conditioning (RIC).

Sixty-one percent of patients had chronic graft-vs-host disease (cGVHD), and 32% had high-risk disease at the time of HSCT.

Survival

The patients were followed for a median of 16.7 years. Thirty percent (n=192) died after surviving at least 2 years post-HSCT.

The median time to death was 8.3 years (range, 2-29.5), and the median age at death was 49.2 (range, 7.8-69.8). At 20 years from HSCT, the overall survival was 68.6%.

HSCT recipients had a 4.4-fold increased risk of death compared with the age-, sex-, and race-matched general population.

“Non-relapse mortality was the major contributor to late mortality, with infection, second malignancies, and cGVHD being the most common causes of death,” Wu said.

Non-relapse mortality was 20%, and relapse-related mortality was 4%. Eight percent of patients died of infection, 6.3% died of cGVHD, and 3.7% died of second malignancies.

Health outcomes

Patients who were still alive at the time of the study were asked to complete the BMTSS-2 health questionnaire, which was used to examine the risk of grade 3/4 chronic health conditions.


A total of 288 patients completed the questionnaire, as did a sibling comparison group of 404 individuals.

Among the patients, the median age at allo-HSCT was 37.5 (range, 3.6-71.4), and the median duration of follow-up was 13.9 years (range, 2-34.6).

Sixty-two percent of patients received an MRD graft, and 38% had a matched, unrelated donor. Eighty-three percent of patients had TBI-based conditioning, 16% received Bu/Cy, and 2.7% received RIC.

The prevalence of grade 3/4 chronic health conditions was significantly higher among patients than among siblings—38% and 24%, respectively (P<0.0001).

The odds ratio (OR)—adjusted for age, sex, race, and socioeconomic status—was 2.7 (P<0.0001).

The cumulative incidence of any grade 3/4 condition at 20 years after HSCT was 47.2% among patients. Common conditions were diabetes (14.9%), second malignancies (12.6%), and coronary artery disease (10%).

The researchers found the risk of grade 3/4 morbidity was significantly higher for the following patient groups:

• Those age 45 and older (hazard ratio [HR]=3.3, P<0.0001)
• Patients with a matched, unrelated donor (HR=3.0, P<0.0001)
• Those who received peripheral blood or cord blood grafts as opposed to bone marrow (HR=2.7, P=0.006).

(This analysis was adjusted for race/ethnicity, sex, education, household income, insurance, cGVHD, and conditioning regimen).

Lower risk

To identify subpopulations with a reduced risk of long-term morbidity, the researchers calculated the risk in various CML patient groups compared to siblings.

The overall OR for CML patients compared with siblings was 2.7 (P<0.0001).

The OR for patients in first chronic phase who underwent HSCT before the age of 45 and had an MRD was 1.5 (P=0.1).

The OR for CML patients in first chronic phase who underwent HSCT before the age of 45, had an MRD, and received Bu/Cy conditioning was 0.8 (P=0.7).

“[W]e found that patients who received a matched, related donor transplant under the age of 45, with busulfan/cyclophosphamide, carried the same burden of morbidity as the sibling cohort,” Wu said. “These findings could help inform decisions regarding therapeutic options for the management of CML.”

Wu noted that the limited sample size in this study prevented the researchers from examining outcomes with RIC. And a lack of data at analysis prevented them from examining pre-HSCT and post-HSCT management of CML, the interval between diagnosis and HSCT, and the life-long economic burden of allo-HSCT.

However, she said data collection is ongoing, and the researchers hope to address some of these limitations.

*Information presented at the meeting differs from the abstract.

 

 

HSCT preparation

Photo by Chad McNeeley

 

SAN DIEGO—Researchers believe they have identified patients with chronic myeloid leukemia (CML) who are likely to derive long-term benefit from allogeneic hematopoietic stem cell transplant (allo-HSCT).

The researchers found that CML patients have a low risk of long-term morbidity if they undergo HSCT before the age of 45, are conditioned with busulfan and cyclophosphamide (Bu/Cy), and receive a graft from a matched, related donor (MRD).

Jessica Wu, of the University of Alabama at Birmingham, presented these findings at the 2016 ASH Annual Meeting (abstract 823*).

Wu noted that allogeneic HSCT is potentially curative for CML, but this method of treatment has been on the decline since the introduction of tyrosine kinase inhibitors (TKIs). And today, few CML patients undergo allo-HSCT.

She said that although TKIs can induce remission in CML patients, the drugs also fail to eradicate leukemia, can produce side effects that impact patients’ quality of life, and come with a significant financial burden (estimated at $92,000 to $138,000 per patient per year).

With this in mind, Wu and her colleagues set out to determine if certain CML patients might benefit from allo-HSCT long-term. The team also wanted to quantify overall and cause-specific late mortality after allo-HSCT and the long-term burden of severe/life-threatening chronic health conditions after allo-HSCT.

Patient population

The researchers studied 637 CML patients treated with allo-HSCT between 1981 and 2010 at City of Hope in Duarte, California, or the University of Minnesota in Minneapolis/Saint Paul. The patients had to have survived at least 2 years post-transplant.

About 60% of patients were male, and 67% were non-Hispanic white. Their median age at HSCT was 36.4 years, and 65% received an MRD graft. Nineteen percent of patients were transplanted in 1980-1989, 52% were transplanted in 1990-1999, and 29% were transplanted in 2000-2010.

Fifty-eight percent of patients received Cy/total body irradiation (TBI), 18% received Bu/Cy, and 3% received reduced-intensity conditioning (RIC).

Sixty-one percent of patients had chronic graft-vs-host disease (cGVHD), and 32% had high-risk disease at the time of HSCT.

Survival

The patients were followed for a median of 16.7 years. Thirty percent (n=192) died after surviving at least 2 years post-HSCT.

The median time to death was 8.3 years (range, 2-29.5), and the median age at death was 49.2 (range, 7.8-69.8). At 20 years from HSCT, the overall survival was 68.6%.

HSCT recipients had a 4.4-fold increased risk of death compared with the age-, sex-, and race-matched general population.

“Non-relapse mortality was the major contributor to late mortality, with infection, second malignancies, and cGVHD being the most common causes of death,” Wu said.

Non-relapse mortality was 20%, and relapse-related mortality was 4%. Eight percent of patients died of infection, 6.3% died of cGVHD, and 3.7% died of second malignancies.

Health outcomes

Patients who were still alive at the time of the study were asked to complete the BMTSS-2 health questionnaire, which was used to examine the risk of grade 3/4 chronic health conditions.


A total of 288 patients completed the questionnaire, as did a sibling comparison group of 404 individuals.

Among the patients, the median age at allo-HSCT was 37.5 (range, 3.6-71.4), and the median duration of follow-up was 13.9 years (range, 2-34.6).

Sixty-two percent of patients received an MRD graft, and 38% had a matched, unrelated donor. Eighty-three percent of patients had TBI-based conditioning, 16% received Bu/Cy, and 2.7% received RIC.

The prevalence of grade 3/4 chronic health conditions was significantly higher among patients than among siblings—38% and 24%, respectively (P<0.0001).

The odds ratio (OR)—adjusted for age, sex, race, and socioeconomic status—was 2.7 (P<0.0001).

The cumulative incidence of any grade 3/4 condition at 20 years after HSCT was 47.2% among patients. Common conditions were diabetes (14.9%), second malignancies (12.6%), and coronary artery disease (10%).

The researchers found the risk of grade 3/4 morbidity was significantly higher for the following patient groups:

• Those age 45 and older (hazard ratio [HR]=3.3, P<0.0001)
• Patients with a matched, unrelated donor (HR=3.0, P<0.0001)
• Those who received peripheral blood or cord blood grafts as opposed to bone marrow (HR=2.7, P=0.006).

(This analysis was adjusted for race/ethnicity, sex, education, household income, insurance, cGVHD, and conditioning regimen).

Lower risk

To identify subpopulations with a reduced risk of long-term morbidity, the researchers calculated the risk in various CML patient groups compared to siblings.

The overall OR for CML patients compared with siblings was 2.7 (P<0.0001).

The OR for patients in first chronic phase who underwent HSCT before the age of 45 and had an MRD was 1.5 (P=0.1).

The OR for CML patients in first chronic phase who underwent HSCT before the age of 45, had an MRD, and received Bu/Cy conditioning was 0.8 (P=0.7).

“[W]e found that patients who received a matched, related donor transplant under the age of 45, with busulfan/cyclophosphamide, carried the same burden of morbidity as the sibling cohort,” Wu said. “These findings could help inform decisions regarding therapeutic options for the management of CML.”

Wu noted that the limited sample size in this study prevented the researchers from examining outcomes with RIC. And a lack of data at analysis prevented them from examining pre-HSCT and post-HSCT management of CML, the interval between diagnosis and HSCT, and the life-long economic burden of allo-HSCT.

However, she said data collection is ongoing, and the researchers hope to address some of these limitations.

*Information presented at the meeting differs from the abstract.

 

 

HSCT preparation

Photo by Chad McNeeley

 

SAN DIEGO—Researchers believe they have identified patients with chronic myeloid leukemia (CML) who are likely to derive long-term benefit from allogeneic hematopoietic stem cell transplant (allo-HSCT).

The researchers found that CML patients have a low risk of long-term morbidity if they undergo HSCT before the age of 45, are conditioned with busulfan and cyclophosphamide (Bu/Cy), and receive a graft from a matched, related donor (MRD).

Jessica Wu, of the University of Alabama at Birmingham, presented these findings at the 2016 ASH Annual Meeting (abstract 823*).

Wu noted that allogeneic HSCT is potentially curative for CML, but this method of treatment has been on the decline since the introduction of tyrosine kinase inhibitors (TKIs). And today, few CML patients undergo allo-HSCT.

She said that although TKIs can induce remission in CML patients, the drugs also fail to eradicate leukemia, can produce side effects that impact patients’ quality of life, and come with a significant financial burden (estimated at $92,000 to $138,000 per patient per year).

With this in mind, Wu and her colleagues set out to determine if certain CML patients might benefit from allo-HSCT long-term. The team also wanted to quantify overall and cause-specific late mortality after allo-HSCT and the long-term burden of severe/life-threatening chronic health conditions after allo-HSCT.

Patient population

The researchers studied 637 CML patients treated with allo-HSCT between 1981 and 2010 at City of Hope in Duarte, California, or the University of Minnesota in Minneapolis/Saint Paul. The patients had to have survived at least 2 years post-transplant.

About 60% of patients were male, and 67% were non-Hispanic white. Their median age at HSCT was 36.4 years, and 65% received an MRD graft. Nineteen percent of patients were transplanted in 1980-1989, 52% were transplanted in 1990-1999, and 29% were transplanted in 2000-2010.

Fifty-eight percent of patients received Cy/total body irradiation (TBI), 18% received Bu/Cy, and 3% received reduced-intensity conditioning (RIC).

Sixty-one percent of patients had chronic graft-vs-host disease (cGVHD), and 32% had high-risk disease at the time of HSCT.

Survival

The patients were followed for a median of 16.7 years. Thirty percent (n=192) died after surviving at least 2 years post-HSCT.

The median time to death was 8.3 years (range, 2-29.5), and the median age at death was 49.2 (range, 7.8-69.8). At 20 years from HSCT, the overall survival was 68.6%.

HSCT recipients had a 4.4-fold increased risk of death compared with the age-, sex-, and race-matched general population.

“Non-relapse mortality was the major contributor to late mortality, with infection, second malignancies, and cGVHD being the most common causes of death,” Wu said.

Non-relapse mortality was 20%, and relapse-related mortality was 4%. Eight percent of patients died of infection, 6.3% died of cGVHD, and 3.7% died of second malignancies.

Health outcomes

Patients who were still alive at the time of the study were asked to complete the BMTSS-2 health questionnaire, which was used to examine the risk of grade 3/4 chronic health conditions.


A total of 288 patients completed the questionnaire, as did a sibling comparison group of 404 individuals.

Among the patients, the median age at allo-HSCT was 37.5 (range, 3.6-71.4), and the median duration of follow-up was 13.9 years (range, 2-34.6).

Sixty-two percent of patients received an MRD graft, and 38% had a matched, unrelated donor. Eighty-three percent of patients had TBI-based conditioning, 16% received Bu/Cy, and 2.7% received RIC.

The prevalence of grade 3/4 chronic health conditions was significantly higher among patients than among siblings—38% and 24%, respectively (P<0.0001).

The odds ratio (OR)—adjusted for age, sex, race, and socioeconomic status—was 2.7 (P<0.0001).

The cumulative incidence of any grade 3/4 condition at 20 years after HSCT was 47.2% among patients. Common conditions were diabetes (14.9%), second malignancies (12.6%), and coronary artery disease (10%).

The researchers found the risk of grade 3/4 morbidity was significantly higher for the following patient groups:

• Those age 45 and older (hazard ratio [HR]=3.3, P<0.0001)
• Patients with a matched, unrelated donor (HR=3.0, P<0.0001)
• Those who received peripheral blood or cord blood grafts as opposed to bone marrow (HR=2.7, P=0.006).

(This analysis was adjusted for race/ethnicity, sex, education, household income, insurance, cGVHD, and conditioning regimen).

Lower risk

To identify subpopulations with a reduced risk of long-term morbidity, the researchers calculated the risk in various CML patient groups compared to siblings.

The overall OR for CML patients compared with siblings was 2.7 (P<0.0001).

The OR for patients in first chronic phase who underwent HSCT before the age of 45 and had an MRD was 1.5 (P=0.1).

The OR for CML patients in first chronic phase who underwent HSCT before the age of 45, had an MRD, and received Bu/Cy conditioning was 0.8 (P=0.7).

“[W]e found that patients who received a matched, related donor transplant under the age of 45, with busulfan/cyclophosphamide, carried the same burden of morbidity as the sibling cohort,” Wu said. “These findings could help inform decisions regarding therapeutic options for the management of CML.”

Wu noted that the limited sample size in this study prevented the researchers from examining outcomes with RIC. And a lack of data at analysis prevented them from examining pre-HSCT and post-HSCT management of CML, the interval between diagnosis and HSCT, and the life-long economic burden of allo-HSCT.

However, she said data collection is ongoing, and the researchers hope to address some of these limitations.

*Information presented at the meeting differs from the abstract.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Researchers have estimated the global incidence of 32 cancer types and deaths related to these malignancies in 2015.

The group’s data, published in JAMA Oncology, suggest there were 17.5 million cancer cases and 8.7 million cancer deaths last year.

There were 78,000 cases of Hodgkin lymphoma and 24,000 deaths from the disease, as well as 666,000 cases of non-Hodgkin lymphoma (NHL) and 231,000 NHL deaths.

There were 154,000 cases of multiple myeloma and 101,000 deaths from the disease.

And there were 606,000 cases of leukemia, with 353,000 leukemia deaths. This included 161,000 cases of acute lymphoid leukemia (110,000 deaths), 191,000 cases of chronic lymphoid leukemia (61,000 deaths), 190,000 cases of acute myeloid leukemia (147,000 deaths), and 64,000 cases of chronic myeloid leukemia (35,000 deaths).

The data also show that, between 2005 and 2015, cancer cases increased by 33%, mostly due to population aging and growth, plus changes in age-specific cancer rates.

Globally, the odds of developing cancer during a lifetime were 1 in 3 for men and 1 in 4 for women in 2015.

Prostate cancer was the most common cancer in men (1.6 million cases), although tracheal, bronchus, and lung cancer was the leading cause of cancer deaths for men.

Breast cancer was the most common cancer for women (2.4 million cases) and the leading cause of cancer deaths in women.

The most common childhood cancers were leukemia, “other neoplasms,” NHL, and brain and nervous system cancers.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Researchers have estimated the global incidence of 32 cancer types and deaths related to these malignancies in 2015.

The group’s data, published in JAMA Oncology, suggest there were 17.5 million cancer cases and 8.7 million cancer deaths last year.

There were 78,000 cases of Hodgkin lymphoma and 24,000 deaths from the disease, as well as 666,000 cases of non-Hodgkin lymphoma (NHL) and 231,000 NHL deaths.

There were 154,000 cases of multiple myeloma and 101,000 deaths from the disease.

And there were 606,000 cases of leukemia, with 353,000 leukemia deaths. This included 161,000 cases of acute lymphoid leukemia (110,000 deaths), 191,000 cases of chronic lymphoid leukemia (61,000 deaths), 190,000 cases of acute myeloid leukemia (147,000 deaths), and 64,000 cases of chronic myeloid leukemia (35,000 deaths).

The data also show that, between 2005 and 2015, cancer cases increased by 33%, mostly due to population aging and growth, plus changes in age-specific cancer rates.

Globally, the odds of developing cancer during a lifetime were 1 in 3 for men and 1 in 4 for women in 2015.

Prostate cancer was the most common cancer in men (1.6 million cases), although tracheal, bronchus, and lung cancer was the leading cause of cancer deaths for men.

Breast cancer was the most common cancer for women (2.4 million cases) and the leading cause of cancer deaths in women.

The most common childhood cancers were leukemia, “other neoplasms,” NHL, and brain and nervous system cancers.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Researchers have estimated the global incidence of 32 cancer types and deaths related to these malignancies in 2015.

The group’s data, published in JAMA Oncology, suggest there were 17.5 million cancer cases and 8.7 million cancer deaths last year.

There were 78,000 cases of Hodgkin lymphoma and 24,000 deaths from the disease, as well as 666,000 cases of non-Hodgkin lymphoma (NHL) and 231,000 NHL deaths.

There were 154,000 cases of multiple myeloma and 101,000 deaths from the disease.

And there were 606,000 cases of leukemia, with 353,000 leukemia deaths. This included 161,000 cases of acute lymphoid leukemia (110,000 deaths), 191,000 cases of chronic lymphoid leukemia (61,000 deaths), 190,000 cases of acute myeloid leukemia (147,000 deaths), and 64,000 cases of chronic myeloid leukemia (35,000 deaths).

The data also show that, between 2005 and 2015, cancer cases increased by 33%, mostly due to population aging and growth, plus changes in age-specific cancer rates.

Globally, the odds of developing cancer during a lifetime were 1 in 3 for men and 1 in 4 for women in 2015.

Prostate cancer was the most common cancer in men (1.6 million cases), although tracheal, bronchus, and lung cancer was the leading cause of cancer deaths for men.

Breast cancer was the most common cancer for women (2.4 million cases) and the leading cause of cancer deaths in women.

The most common childhood cancers were leukemia, “other neoplasms,” NHL, and brain and nervous system cancers.

Francois-Xavier Mahon, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.

About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.

Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).

Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.

“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”

Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.

Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.

At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.

Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.

Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”

Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.

The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.

*Information presented at the meeting differs from the abstract.

Francois-Xavier Mahon, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.

About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.

Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).

Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.

“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”

Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.

Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.

At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.

Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.

Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”

Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.

The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.

*Information presented at the meeting differs from the abstract.

Francois-Xavier Mahon, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.

About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.

Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).

Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.

“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”

Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.

Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.

At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.

Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.

Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”

Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.

The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.

*Information presented at the meeting differs from the abstract.

SAN DIEGO – Tyrosine kinase inhibitors have dramatically improved survival for patients with chronic myeloid leukemia, but for some patients with solid stable remissions, halving the TKI dose or even stopping therapy altogether, at least temporarily, appears to be safe and to offer both health and financial benefits,

In the British Destiny [De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel (dasatinib)], there were 12 molecular relapses occurring between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all patients had restoration of molecular remissions after resumption of full dose TKIs.

Coinvestigator Mhairi Copland, MD, PhD, of the University of Glasgow, Scotland, discussed in a video interview the potential clinical benefits of lower-dose therapy in patients in stable CML remissions, and notes that de-escalation strategy is associated with a nearly 50% saving in costs compared with full-dose TKI therapy.

SAN DIEGO – Tyrosine kinase inhibitors have dramatically improved survival for patients with chronic myeloid leukemia, but for some patients with solid stable remissions, halving the TKI dose or even stopping therapy altogether, at least temporarily, appears to be safe and to offer both health and financial benefits,

In the British Destiny [De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel (dasatinib)], there were 12 molecular relapses occurring between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all patients had restoration of molecular remissions after resumption of full dose TKIs.

Coinvestigator Mhairi Copland, MD, PhD, of the University of Glasgow, Scotland, discussed in a video interview the potential clinical benefits of lower-dose therapy in patients in stable CML remissions, and notes that de-escalation strategy is associated with a nearly 50% saving in costs compared with full-dose TKI therapy.

SAN DIEGO – Tyrosine kinase inhibitors have dramatically improved survival for patients with chronic myeloid leukemia, but for some patients with solid stable remissions, halving the TKI dose or even stopping therapy altogether, at least temporarily, appears to be safe and to offer both health and financial benefits,

In the British Destiny [De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel (dasatinib)], there were 12 molecular relapses occurring between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all patients had restoration of molecular remissions after resumption of full dose TKIs.

Coinvestigator Mhairi Copland, MD, PhD, of the University of Glasgow, Scotland, discussed in a video interview the potential clinical benefits of lower-dose therapy in patients in stable CML remissions, and notes that de-escalation strategy is associated with a nearly 50% saving in costs compared with full-dose TKI therapy.

SAN DIEGO – For some chronic myeloid leukemia patients with solid, stable remissions, halving their dose of a tyrosine kinase inhibitor – or even stopping therapy altogether, at least temporarily – appears to be safe and to offer both health and financial benefits, European investigators said at the annual meeting of the American Society of Hematology.

In the British De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel [dasatinib], or Destiny Study, a total of 12 molecular relapses occurred between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all 12 patients had restoration of molecular remissions after resumption of full dose TKIs, reported co-investigator Mhairi Copland, MD, PhD, from the University of Glasgow, Scotland.

All 12 patients who experienced molecular recurrence regained MR3 within 4 months of resuming TKI therapy at the full dose.

As noted before, patient-reported side effects such as lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning decreased during the first 3 months of de-escalation, but not thereafter. Dr. Copland said that patients had generally good quality-of-life scores at study entry, suggesting that they were likely not especially bothered by TKI side effects in the first place.

The investigators calculated that for the 174 patients, halving treatment would save an estimated £1,943,364 ($2,474,679) from an expected TKI budget of £4,156,969 ($5,293,484), a savings of 46.7%. Estimated savings were similar for patients with MR4 or better alone (47.7%) and for those with a major molecular response (44.2%).

EURO-SKI Update

Also at ASH 2016, Francois-Xavier Mahon, MD, PhD, from the University of Bordeaux, France, reported additional follow-up data from the EURO-SKI trial, results of which were first reported at the 2016 annual meeting of the European Hematology Association in Copenhagen.

The investigators found that 50% of 755 assessable patients with CML were free of molecular recurrence at 24 months, as were 47% at 36 months.

As reported previously, patients who had been on a TKI for more than 5.8 years before attempting to stop had a lower rate of relapse (34.5%) than patients who had been on therapy for less than 5.8 years (57.4%). Each additional year of TKI therapy was associated with an approximately 16% better chance of successful TKI cessation.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr. Mahon said at the briefing.

The British Destiny Study was supported by Newcastle University. Dr. Copland reported honoraria, advisory board memberships, and/or research funding from Amgen, Pfizer, Shire, BMS, and Ariad.

EURO-SKI was sponsored by the European LeukemiaNet. Dr. Mahon has previously disclosed being on the scientific advisory board and receiving honoraria from Novartis Oncology and BMS, and serving as consultant to those companies and to Pfizer.

SAN DIEGO – For some chronic myeloid leukemia patients with solid, stable remissions, halving their dose of a tyrosine kinase inhibitor – or even stopping therapy altogether, at least temporarily – appears to be safe and to offer both health and financial benefits, European investigators said at the annual meeting of the American Society of Hematology.

In the British De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel [dasatinib], or Destiny Study, a total of 12 molecular relapses occurred between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all 12 patients had restoration of molecular remissions after resumption of full dose TKIs, reported co-investigator Mhairi Copland, MD, PhD, from the University of Glasgow, Scotland.

All 12 patients who experienced molecular recurrence regained MR3 within 4 months of resuming TKI therapy at the full dose.

As noted before, patient-reported side effects such as lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning decreased during the first 3 months of de-escalation, but not thereafter. Dr. Copland said that patients had generally good quality-of-life scores at study entry, suggesting that they were likely not especially bothered by TKI side effects in the first place.

The investigators calculated that for the 174 patients, halving treatment would save an estimated £1,943,364 ($2,474,679) from an expected TKI budget of £4,156,969 ($5,293,484), a savings of 46.7%. Estimated savings were similar for patients with MR4 or better alone (47.7%) and for those with a major molecular response (44.2%).

EURO-SKI Update

Also at ASH 2016, Francois-Xavier Mahon, MD, PhD, from the University of Bordeaux, France, reported additional follow-up data from the EURO-SKI trial, results of which were first reported at the 2016 annual meeting of the European Hematology Association in Copenhagen.

The investigators found that 50% of 755 assessable patients with CML were free of molecular recurrence at 24 months, as were 47% at 36 months.

As reported previously, patients who had been on a TKI for more than 5.8 years before attempting to stop had a lower rate of relapse (34.5%) than patients who had been on therapy for less than 5.8 years (57.4%). Each additional year of TKI therapy was associated with an approximately 16% better chance of successful TKI cessation.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr. Mahon said at the briefing.

The British Destiny Study was supported by Newcastle University. Dr. Copland reported honoraria, advisory board memberships, and/or research funding from Amgen, Pfizer, Shire, BMS, and Ariad.

EURO-SKI was sponsored by the European LeukemiaNet. Dr. Mahon has previously disclosed being on the scientific advisory board and receiving honoraria from Novartis Oncology and BMS, and serving as consultant to those companies and to Pfizer.

SAN DIEGO – For some chronic myeloid leukemia patients with solid, stable remissions, halving their dose of a tyrosine kinase inhibitor – or even stopping therapy altogether, at least temporarily – appears to be safe and to offer both health and financial benefits, European investigators said at the annual meeting of the American Society of Hematology.

In the British De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel [dasatinib], or Destiny Study, a total of 12 molecular relapses occurred between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all 12 patients had restoration of molecular remissions after resumption of full dose TKIs, reported co-investigator Mhairi Copland, MD, PhD, from the University of Glasgow, Scotland.

All 12 patients who experienced molecular recurrence regained MR3 within 4 months of resuming TKI therapy at the full dose.

As noted before, patient-reported side effects such as lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning decreased during the first 3 months of de-escalation, but not thereafter. Dr. Copland said that patients had generally good quality-of-life scores at study entry, suggesting that they were likely not especially bothered by TKI side effects in the first place.

The investigators calculated that for the 174 patients, halving treatment would save an estimated £1,943,364 ($2,474,679) from an expected TKI budget of £4,156,969 ($5,293,484), a savings of 46.7%. Estimated savings were similar for patients with MR4 or better alone (47.7%) and for those with a major molecular response (44.2%).

EURO-SKI Update

Also at ASH 2016, Francois-Xavier Mahon, MD, PhD, from the University of Bordeaux, France, reported additional follow-up data from the EURO-SKI trial, results of which were first reported at the 2016 annual meeting of the European Hematology Association in Copenhagen.

The investigators found that 50% of 755 assessable patients with CML were free of molecular recurrence at 24 months, as were 47% at 36 months.

As reported previously, patients who had been on a TKI for more than 5.8 years before attempting to stop had a lower rate of relapse (34.5%) than patients who had been on therapy for less than 5.8 years (57.4%). Each additional year of TKI therapy was associated with an approximately 16% better chance of successful TKI cessation.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr. Mahon said at the briefing.

The British Destiny Study was supported by Newcastle University. Dr. Copland reported honoraria, advisory board memberships, and/or research funding from Amgen, Pfizer, Shire, BMS, and Ariad.

EURO-SKI was sponsored by the European LeukemiaNet. Dr. Mahon has previously disclosed being on the scientific advisory board and receiving honoraria from Novartis Oncology and BMS, and serving as consultant to those companies and to Pfizer.

Ponatinib (Iclusig)

Photo from Business Wire

The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.

Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.

Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.

Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.

This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.

The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.

“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.

“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”

Past problems with ponatinib

Previous follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the US and European Union, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the FDA evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the drug. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.

Ponatinib (Iclusig)

Photo from Business Wire

The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.

Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.

Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.

Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.

This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.

The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.

“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.

“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”

Past problems with ponatinib

Previous follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the US and European Union, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the FDA evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the drug. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.

Ponatinib (Iclusig)

Photo from Business Wire

The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.

Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.

Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.

Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.

This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.

The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.

“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.

“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”

Past problems with ponatinib

Previous follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the US and European Union, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the FDA evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the drug. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.

A cell-based BCR-ABL1 secondary reference panel traceable to the World Health Organization BCR-ABL1 International Genetic Reference Panel – with an additional MR4.5 level – provides easier access to International Scale calibration and can act as a tool for assay optimization, validation, and quality assurance for molecular monitoring in chronic myeloid leukemia patients.

Such monitoring is important to disease management, especially for decision making with respect to treatment cessation. The new secondary reference panel would allow laboratories to circumvent the oft-used and time-consuming sample exchange process with reference laboratories for International Scale (IS) calibration, Nicholas C. P. Cross, PhD, of the University of Southampton (England) and colleagues wrote in an article published in Leukemia (2016 Jun 3;30:1844-52).

“The development of BCR-ABL1 tyrosine kinase inhibitors ... has enabled progressively deeper molecular responses in CML patients undergoing tyrosine kinase inhibitor therapy,” the authors wrote, noting that deeper molecular responses are “important milestones for patients considering treatment cessation,” and that “other landmarks on the IS also represent different treatment decision thresholds and prognostic outcomes.”

For this reason, regular molecular monitoring using real-time reverse-transcription quantitative PCR (RqPCR) is recommended for optimal disease management, they said.

“As treatment decisions are directly impacted by test results, accuracy and precision of BCR-ABL1 assays across the entire measurement range is crucial for patient management, especially in patients with deep molecular responses when considering possible treatment cessation,” they wrote.

Access to the material for the WHO BCR-ABL1 reference panel (MR1-MR4), which was developed in 2010 as a primary standard for BCR-ABL1 assay IS calibration, is limited, particularly for smaller laboratories, the authors said.

The secondary reference panel they developed, however, is “traceable to and faithfully replicates the WHO panel in both raw materials (lyopholized.K562 and HL-60 cell mixes) and manufacturing process, with the addition of a MR4.5 level.” The secondary panel was calibrated to IS using digital PCR against ABL1, BCR, and GUSB as reference genes, and was successfully evaluated by 45 different BCR-ABL1 assays at 44 different clinical laboratories in a multinational evaluation study.

The MR4.5 level was added to allow for more accurate IS calibration “as CML patients reaching this deep molecular response are increasingly being considered for treatment cessation,” the authors noted.

“Quality-control assessments indicated that the secondary panel had minimal residual moisture, excellent vial-to-vial homogeneity and greater than 2.5 years of real-time stability,” they said.

Further, the panel was successfully processed by all of the laboratories, indicating that it is compatible with many different BCR-ABL1 test configurations, they added.

Of note, the number of assays that achieved good precision and sensitivity exceeded the number that achieved good IS accuracy, suggesting an unmet need for “a simple and broadly available calibration mechanism, such as this secondary panel, to ensure IS accuracy is maintained in laboratories over time,” they wrote, concluding that such a panel “can provide easier access to IS calibration, as well as act as a tool for assay optimization, validation and quality assurance.”

In a letter to the editor in regard to the findings by Cross et al., Maria Sol Ruiz of Instituto Alexander Fleming in Buenos Aires, and colleagues wrote about their own development and validation of “secondary reference materials calibrated to the IS through the WHO primary standards in order to facilitate standardization of molecular monitoring in Latin America,” (Leukemia. 2016 Aug 19. doi: 10.1038/leu.2016.197).

In their study, the letter’s authors demonstrated that secondary reference biological calibrators anchored to the WHO primary standards can decrease inter-laboratory variability.

“Our results, together with those recently reported by Cross et al., substantiate the objective initially set during the establishment of the WHO primary standards, that is, to facilitate worldwide diffusion of the IS. For the first time in Latin America, this study provides a platform on which to assess the performance of distinct clinical BCR-ABL1 tests and confirm the utility of secondary reference materials to further improve IS accuracy and inter-laboratory precision,” they wrote, noting that their efforts will continue through provision of secondary reference material to centers involved in their project, as well as to potential new participants.

“Moreover, due to its higher precision and absolute quantification capability, we are evaluating the possibility of including digital PCR as the calibration method for the future,” they said.

The study discussed in the letter to the editor was supported by a grant from Novartis to one of the authors. Novartis also paid speaking fees to some of the authors. The study by Dr. Cross et al. was also funded by Novartis and some authors are employed by Novartis. The remaining authors, including Dr. Cross, reported having no disclosures.

[email protected]

A cell-based BCR-ABL1 secondary reference panel traceable to the World Health Organization BCR-ABL1 International Genetic Reference Panel – with an additional MR4.5 level – provides easier access to International Scale calibration and can act as a tool for assay optimization, validation, and quality assurance for molecular monitoring in chronic myeloid leukemia patients.

Such monitoring is important to disease management, especially for decision making with respect to treatment cessation. The new secondary reference panel would allow laboratories to circumvent the oft-used and time-consuming sample exchange process with reference laboratories for International Scale (IS) calibration, Nicholas C. P. Cross, PhD, of the University of Southampton (England) and colleagues wrote in an article published in Leukemia (2016 Jun 3;30:1844-52).

“The development of BCR-ABL1 tyrosine kinase inhibitors ... has enabled progressively deeper molecular responses in CML patients undergoing tyrosine kinase inhibitor therapy,” the authors wrote, noting that deeper molecular responses are “important milestones for patients considering treatment cessation,” and that “other landmarks on the IS also represent different treatment decision thresholds and prognostic outcomes.”

For this reason, regular molecular monitoring using real-time reverse-transcription quantitative PCR (RqPCR) is recommended for optimal disease management, they said.

“As treatment decisions are directly impacted by test results, accuracy and precision of BCR-ABL1 assays across the entire measurement range is crucial for patient management, especially in patients with deep molecular responses when considering possible treatment cessation,” they wrote.

Access to the material for the WHO BCR-ABL1 reference panel (MR1-MR4), which was developed in 2010 as a primary standard for BCR-ABL1 assay IS calibration, is limited, particularly for smaller laboratories, the authors said.

The secondary reference panel they developed, however, is “traceable to and faithfully replicates the WHO panel in both raw materials (lyopholized.K562 and HL-60 cell mixes) and manufacturing process, with the addition of a MR4.5 level.” The secondary panel was calibrated to IS using digital PCR against ABL1, BCR, and GUSB as reference genes, and was successfully evaluated by 45 different BCR-ABL1 assays at 44 different clinical laboratories in a multinational evaluation study.

The MR4.5 level was added to allow for more accurate IS calibration “as CML patients reaching this deep molecular response are increasingly being considered for treatment cessation,” the authors noted.

“Quality-control assessments indicated that the secondary panel had minimal residual moisture, excellent vial-to-vial homogeneity and greater than 2.5 years of real-time stability,” they said.

Further, the panel was successfully processed by all of the laboratories, indicating that it is compatible with many different BCR-ABL1 test configurations, they added.

Of note, the number of assays that achieved good precision and sensitivity exceeded the number that achieved good IS accuracy, suggesting an unmet need for “a simple and broadly available calibration mechanism, such as this secondary panel, to ensure IS accuracy is maintained in laboratories over time,” they wrote, concluding that such a panel “can provide easier access to IS calibration, as well as act as a tool for assay optimization, validation and quality assurance.”

In a letter to the editor in regard to the findings by Cross et al., Maria Sol Ruiz of Instituto Alexander Fleming in Buenos Aires, and colleagues wrote about their own development and validation of “secondary reference materials calibrated to the IS through the WHO primary standards in order to facilitate standardization of molecular monitoring in Latin America,” (Leukemia. 2016 Aug 19. doi: 10.1038/leu.2016.197).

In their study, the letter’s authors demonstrated that secondary reference biological calibrators anchored to the WHO primary standards can decrease inter-laboratory variability.

“Our results, together with those recently reported by Cross et al., substantiate the objective initially set during the establishment of the WHO primary standards, that is, to facilitate worldwide diffusion of the IS. For the first time in Latin America, this study provides a platform on which to assess the performance of distinct clinical BCR-ABL1 tests and confirm the utility of secondary reference materials to further improve IS accuracy and inter-laboratory precision,” they wrote, noting that their efforts will continue through provision of secondary reference material to centers involved in their project, as well as to potential new participants.

“Moreover, due to its higher precision and absolute quantification capability, we are evaluating the possibility of including digital PCR as the calibration method for the future,” they said.

The study discussed in the letter to the editor was supported by a grant from Novartis to one of the authors. Novartis also paid speaking fees to some of the authors. The study by Dr. Cross et al. was also funded by Novartis and some authors are employed by Novartis. The remaining authors, including Dr. Cross, reported having no disclosures.

[email protected]

A cell-based BCR-ABL1 secondary reference panel traceable to the World Health Organization BCR-ABL1 International Genetic Reference Panel – with an additional MR4.5 level – provides easier access to International Scale calibration and can act as a tool for assay optimization, validation, and quality assurance for molecular monitoring in chronic myeloid leukemia patients.

Such monitoring is important to disease management, especially for decision making with respect to treatment cessation. The new secondary reference panel would allow laboratories to circumvent the oft-used and time-consuming sample exchange process with reference laboratories for International Scale (IS) calibration, Nicholas C. P. Cross, PhD, of the University of Southampton (England) and colleagues wrote in an article published in Leukemia (2016 Jun 3;30:1844-52).

“The development of BCR-ABL1 tyrosine kinase inhibitors ... has enabled progressively deeper molecular responses in CML patients undergoing tyrosine kinase inhibitor therapy,” the authors wrote, noting that deeper molecular responses are “important milestones for patients considering treatment cessation,” and that “other landmarks on the IS also represent different treatment decision thresholds and prognostic outcomes.”

For this reason, regular molecular monitoring using real-time reverse-transcription quantitative PCR (RqPCR) is recommended for optimal disease management, they said.

“As treatment decisions are directly impacted by test results, accuracy and precision of BCR-ABL1 assays across the entire measurement range is crucial for patient management, especially in patients with deep molecular responses when considering possible treatment cessation,” they wrote.

Access to the material for the WHO BCR-ABL1 reference panel (MR1-MR4), which was developed in 2010 as a primary standard for BCR-ABL1 assay IS calibration, is limited, particularly for smaller laboratories, the authors said.

The secondary reference panel they developed, however, is “traceable to and faithfully replicates the WHO panel in both raw materials (lyopholized.K562 and HL-60 cell mixes) and manufacturing process, with the addition of a MR4.5 level.” The secondary panel was calibrated to IS using digital PCR against ABL1, BCR, and GUSB as reference genes, and was successfully evaluated by 45 different BCR-ABL1 assays at 44 different clinical laboratories in a multinational evaluation study.

The MR4.5 level was added to allow for more accurate IS calibration “as CML patients reaching this deep molecular response are increasingly being considered for treatment cessation,” the authors noted.

“Quality-control assessments indicated that the secondary panel had minimal residual moisture, excellent vial-to-vial homogeneity and greater than 2.5 years of real-time stability,” they said.

Further, the panel was successfully processed by all of the laboratories, indicating that it is compatible with many different BCR-ABL1 test configurations, they added.

Of note, the number of assays that achieved good precision and sensitivity exceeded the number that achieved good IS accuracy, suggesting an unmet need for “a simple and broadly available calibration mechanism, such as this secondary panel, to ensure IS accuracy is maintained in laboratories over time,” they wrote, concluding that such a panel “can provide easier access to IS calibration, as well as act as a tool for assay optimization, validation and quality assurance.”

In a letter to the editor in regard to the findings by Cross et al., Maria Sol Ruiz of Instituto Alexander Fleming in Buenos Aires, and colleagues wrote about their own development and validation of “secondary reference materials calibrated to the IS through the WHO primary standards in order to facilitate standardization of molecular monitoring in Latin America,” (Leukemia. 2016 Aug 19. doi: 10.1038/leu.2016.197).

In their study, the letter’s authors demonstrated that secondary reference biological calibrators anchored to the WHO primary standards can decrease inter-laboratory variability.

“Our results, together with those recently reported by Cross et al., substantiate the objective initially set during the establishment of the WHO primary standards, that is, to facilitate worldwide diffusion of the IS. For the first time in Latin America, this study provides a platform on which to assess the performance of distinct clinical BCR-ABL1 tests and confirm the utility of secondary reference materials to further improve IS accuracy and inter-laboratory precision,” they wrote, noting that their efforts will continue through provision of secondary reference material to centers involved in their project, as well as to potential new participants.

“Moreover, due to its higher precision and absolute quantification capability, we are evaluating the possibility of including digital PCR as the calibration method for the future,” they said.

The study discussed in the letter to the editor was supported by a grant from Novartis to one of the authors. Novartis also paid speaking fees to some of the authors. The study by Dr. Cross et al. was also funded by Novartis and some authors are employed by Novartis. The remaining authors, including Dr. Cross, reported having no disclosures.

[email protected]

CML cells

Image by Difu Wu

Targeting a pair of transcription factors might improve the treatment of chronic myeloid leukemia (CML), according to researchers.

The team found that p53 and c-MYC have “defining roles” in the survival of leukemia stem cells (LSCs) in CML.

And by targeting these transcription factors with a pair of investigational drugs, the researchers were able to kill LSCs.

The team described this work in Nature.

“This collaborative study combined proteomics, transcriptomics, and systems biology to identify a novel, precision medicine-based approach for eradicating leukemic stem cells,” said study author Tony Whetton, PhD, of the University of Manchester in the UK.

Dr Whetton and his colleagues first discovered that p53 and c-MYC are “central hubs” in a CML network of deregulated proteins. The team also found that CML cells express increased c-MYC and decreased p53 levels.

So the researchers theorized that simultaneously activating p53 and inhibiting c-MYC could be a method for treating CML.

To that end, the team tested 2 drugs—RITA (or NSC652287), which binds p53 and blocks its degradation, and CPI-203, a BET inhibitor that hinders transcription by disrupting chromatin-dependent signal transduction.

The researchers found that CPI-203 successfully downregulated c-MYC but also reduced p53, while RITA increased p53.

Treating CML CD34+ cells with RITA or CPI-203 for 72 hours reduced cell viability and induced significant apoptosis, the team said. Combining the drugs enhanced these effects.

The researchers also found evidence to suggest that c-MYC inhibition induces differentiation of CML CD34+ cells. The team said that labelling with the cell-division tracker carboxyfluorescein succinimidyl ester (CFSE) and CD34 antibody showed that, as CML cells divided in the presence of CPI-203, there was a clear and rapid loss of CD34 expression that was not seen in the presence of RITA.

The researchers did not observe any differences in the effects of RITA and CPI-203 when they were tested in CML CD34+ cells pretreated with imatinib.

Furthermore, RITA and CPI-203, either alone or in combination, had no significant effects on normal CD34+ cells when tested at lower concentrations. However, when CPI-203 was used alone at higher concentrations (2 or 5 μ M) or with RITA at the highest concentrations tested (RITA at 25 nM, CPI-203 at 5 μ M), apoptosis did occur.

In CML cells, the researchers observed “significant apoptosis” with all concentrations of CPI-203 and RITA tested.

The team also exposed CML LSCs, defined as either CFSE^max or CD34+CD38− cells, to CPI-203 and RITA as well as a pair of tyrosine kinase inhibitors.

The CFSE^max population persisted despite 5 days of treatment with dasatinib or nilotinib, but the cells were “significantly reduced” after 5 days of treatment with CPI-203 alone and in combination with RITA.

Similarly, 72 hours of treatment with RITA with CPI-203 eliminated residual CD34+CD38− cells.

The researchers also assessed LSC engraftment after treatment with RITA and/or CPI-203, as well as dasatinib. They exposed CML CD34+ cells to the drugs for 48 hours before transplanting the cells into sublethally irradiated NSG mice.

The team said dasatinib had no significant effect on NSG-repopulating CML LSCs. However, RITA, CPI-203, and the drugs in combination reduced engraftment, as indicated by decreased CD45+, CD34+, CD33+, CD11b+, CD19+ and CD14+ cells.

CML cells

Image by Difu Wu

Targeting a pair of transcription factors might improve the treatment of chronic myeloid leukemia (CML), according to researchers.

The team found that p53 and c-MYC have “defining roles” in the survival of leukemia stem cells (LSCs) in CML.

And by targeting these transcription factors with a pair of investigational drugs, the researchers were able to kill LSCs.

The team described this work in Nature.

“This collaborative study combined proteomics, transcriptomics, and systems biology to identify a novel, precision medicine-based approach for eradicating leukemic stem cells,” said study author Tony Whetton, PhD, of the University of Manchester in the UK.

Dr Whetton and his colleagues first discovered that p53 and c-MYC are “central hubs” in a CML network of deregulated proteins. The team also found that CML cells express increased c-MYC and decreased p53 levels.

So the researchers theorized that simultaneously activating p53 and inhibiting c-MYC could be a method for treating CML.

To that end, the team tested 2 drugs—RITA (or NSC652287), which binds p53 and blocks its degradation, and CPI-203, a BET inhibitor that hinders transcription by disrupting chromatin-dependent signal transduction.

The researchers found that CPI-203 successfully downregulated c-MYC but also reduced p53, while RITA increased p53.

Treating CML CD34+ cells with RITA or CPI-203 for 72 hours reduced cell viability and induced significant apoptosis, the team said. Combining the drugs enhanced these effects.

The researchers also found evidence to suggest that c-MYC inhibition induces differentiation of CML CD34+ cells. The team said that labelling with the cell-division tracker carboxyfluorescein succinimidyl ester (CFSE) and CD34 antibody showed that, as CML cells divided in the presence of CPI-203, there was a clear and rapid loss of CD34 expression that was not seen in the presence of RITA.

The researchers did not observe any differences in the effects of RITA and CPI-203 when they were tested in CML CD34+ cells pretreated with imatinib.

Furthermore, RITA and CPI-203, either alone or in combination, had no significant effects on normal CD34+ cells when tested at lower concentrations. However, when CPI-203 was used alone at higher concentrations (2 or 5 μ M) or with RITA at the highest concentrations tested (RITA at 25 nM, CPI-203 at 5 μ M), apoptosis did occur.

In CML cells, the researchers observed “significant apoptosis” with all concentrations of CPI-203 and RITA tested.

The team also exposed CML LSCs, defined as either CFSE^max or CD34+CD38− cells, to CPI-203 and RITA as well as a pair of tyrosine kinase inhibitors.

The CFSE^max population persisted despite 5 days of treatment with dasatinib or nilotinib, but the cells were “significantly reduced” after 5 days of treatment with CPI-203 alone and in combination with RITA.

Similarly, 72 hours of treatment with RITA with CPI-203 eliminated residual CD34+CD38− cells.

The researchers also assessed LSC engraftment after treatment with RITA and/or CPI-203, as well as dasatinib. They exposed CML CD34+ cells to the drugs for 48 hours before transplanting the cells into sublethally irradiated NSG mice.

The team said dasatinib had no significant effect on NSG-repopulating CML LSCs. However, RITA, CPI-203, and the drugs in combination reduced engraftment, as indicated by decreased CD45+, CD34+, CD33+, CD11b+, CD19+ and CD14+ cells.

CML cells

Image by Difu Wu

Targeting a pair of transcription factors might improve the treatment of chronic myeloid leukemia (CML), according to researchers.

The team found that p53 and c-MYC have “defining roles” in the survival of leukemia stem cells (LSCs) in CML.

And by targeting these transcription factors with a pair of investigational drugs, the researchers were able to kill LSCs.

The team described this work in Nature.

“This collaborative study combined proteomics, transcriptomics, and systems biology to identify a novel, precision medicine-based approach for eradicating leukemic stem cells,” said study author Tony Whetton, PhD, of the University of Manchester in the UK.

Dr Whetton and his colleagues first discovered that p53 and c-MYC are “central hubs” in a CML network of deregulated proteins. The team also found that CML cells express increased c-MYC and decreased p53 levels.

So the researchers theorized that simultaneously activating p53 and inhibiting c-MYC could be a method for treating CML.

To that end, the team tested 2 drugs—RITA (or NSC652287), which binds p53 and blocks its degradation, and CPI-203, a BET inhibitor that hinders transcription by disrupting chromatin-dependent signal transduction.

The researchers found that CPI-203 successfully downregulated c-MYC but also reduced p53, while RITA increased p53.

Treating CML CD34+ cells with RITA or CPI-203 for 72 hours reduced cell viability and induced significant apoptosis, the team said. Combining the drugs enhanced these effects.

The researchers also found evidence to suggest that c-MYC inhibition induces differentiation of CML CD34+ cells. The team said that labelling with the cell-division tracker carboxyfluorescein succinimidyl ester (CFSE) and CD34 antibody showed that, as CML cells divided in the presence of CPI-203, there was a clear and rapid loss of CD34 expression that was not seen in the presence of RITA.

The researchers did not observe any differences in the effects of RITA and CPI-203 when they were tested in CML CD34+ cells pretreated with imatinib.

Furthermore, RITA and CPI-203, either alone or in combination, had no significant effects on normal CD34+ cells when tested at lower concentrations. However, when CPI-203 was used alone at higher concentrations (2 or 5 μ M) or with RITA at the highest concentrations tested (RITA at 25 nM, CPI-203 at 5 μ M), apoptosis did occur.

In CML cells, the researchers observed “significant apoptosis” with all concentrations of CPI-203 and RITA tested.

The team also exposed CML LSCs, defined as either CFSE^max or CD34+CD38− cells, to CPI-203 and RITA as well as a pair of tyrosine kinase inhibitors.

The CFSE^max population persisted despite 5 days of treatment with dasatinib or nilotinib, but the cells were “significantly reduced” after 5 days of treatment with CPI-203 alone and in combination with RITA.

Similarly, 72 hours of treatment with RITA with CPI-203 eliminated residual CD34+CD38− cells.

The researchers also assessed LSC engraftment after treatment with RITA and/or CPI-203, as well as dasatinib. They exposed CML CD34+ cells to the drugs for 48 hours before transplanting the cells into sublethally irradiated NSG mice.

The team said dasatinib had no significant effect on NSG-repopulating CML LSCs. However, RITA, CPI-203, and the drugs in combination reduced engraftment, as indicated by decreased CD45+, CD34+, CD33+, CD11b+, CD19+ and CD14+ cells.

Burkitt lymphoma

Image by Ed Uthman

A new compound has shown promise for treating hematologic malignancies and other cancers, according to preclinical research published in Nature.

The compound, known as S63845, targets the BCL2 family protein MCL1.

Investigators said their research on S63845 provides the first clear evidence that inhibiting MCL1 is effective in targeting several cancer types, including leukemia, lymphoma, and multiple myeloma (MM).

“MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body,” said study author Guillaume Lessene, PhD, of the Walter and Eliza Hall Institute in Melbourne, Australia.

“Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival.”

About S63845

Dr Lessene and his colleagues said S63845 binds with high affinity to the BH3-binding groove of MCL1. And the compound kills MCL1-dependent cancer cells by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.

In solid tumors, S63845 often wasn’t effective enough on its own. However, when the compound was combined with various kinase inhibitors, it induced a “potent cytotoxic response” in breast cancer, lung cancer, and melanoma cells.

In hematologic malignancies, S63845 proved effective when given alone.

Myeloma

The investigators said 17 of 25 MM cell lines tested were highly sensitive to S63845 (IC₅₀ < 0.1 μ M), 6 cell lines were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 2 cell lines were insensitive (IC₅₀ > 1 μ M).

The team also administered S63845 (at 25 mg/kg) to mice with MM. Seven of 8 mice had complete regression at 100 days after treatment.

Lymphoma

The investigators tested S63845 in 11 cell lines representative of human lymphomas. Five were highly sensitive to the compound (IC₅₀ < 0.1 μ M), 3 were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 3 were insensitive (IC₅₀ > 1 μ M).

The team also tested S63845 in 7 c-MYC-driven human Burkitt lymphoma cell lines and found the compound exhibited “potent cytotoxic activity” in all of them.

The investigators then tested S63845 in a c-MYC-driven mouse lymphoma model. They noted that both tumor cells and normal tissues express mouse MCL1 protein in this model.

Treatment with S63845 (25 mg/kg) for 5 consecutive days cured 70% of these mice, and the investigators said there were no evident side effects in normal tissues.

Leukemia

The investigators tested S63845 in 5 chronic myeloid leukemia cell lines, and none of them were sensitive to the compound.

However, the team also tested S63845 in 8 acute myeloid leukemia (AML) cell lines, and all of them were sensitive to the compound (IC₅₀ 4–233 nM).

When S63845 was given to mice with AML (25 mg/kg), 6 of the 8 mice achieved complete remission after 80 days.

The investigators also tested S63845 in 25 freshly derived samples from patients with AML. The team said these samples displayed a wide range of responses to S63845.

The most sensitive samples required 100- to 1000-fold less drug (to induce apoptosis) than the resistant samples or normal CD34+ progenitor cells.

Development/funding

S63845 was discovered through a collaboration between 2 pharmaceutical companies—Servier, which is headquartered in France, and Vernalis (R&D), which is based in the UK.

“[C]linical development of a MCL1 inhibitor should be launched in the near future,” said Olivier Geneste, director of oncology research at Servier.

The current research was supported through a collaboration with Servier and through funding from the National Health and Medical Research Council of Australia, the Leukemia and Lymphoma Society, Cancer Council Victoria, the Kay Kendall Leukemia Fund, Victorian Cancer Agency, Australian Cancer Research Foundation, the Victorian Government Operational Infrastructure Scheme, and the estate of Anthony Redstone.

Burkitt lymphoma

Image by Ed Uthman

A new compound has shown promise for treating hematologic malignancies and other cancers, according to preclinical research published in Nature.

The compound, known as S63845, targets the BCL2 family protein MCL1.

Investigators said their research on S63845 provides the first clear evidence that inhibiting MCL1 is effective in targeting several cancer types, including leukemia, lymphoma, and multiple myeloma (MM).

“MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body,” said study author Guillaume Lessene, PhD, of the Walter and Eliza Hall Institute in Melbourne, Australia.

“Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival.”

About S63845

Dr Lessene and his colleagues said S63845 binds with high affinity to the BH3-binding groove of MCL1. And the compound kills MCL1-dependent cancer cells by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.

In solid tumors, S63845 often wasn’t effective enough on its own. However, when the compound was combined with various kinase inhibitors, it induced a “potent cytotoxic response” in breast cancer, lung cancer, and melanoma cells.

In hematologic malignancies, S63845 proved effective when given alone.

Myeloma

The investigators said 17 of 25 MM cell lines tested were highly sensitive to S63845 (IC₅₀ < 0.1 μ M), 6 cell lines were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 2 cell lines were insensitive (IC₅₀ > 1 μ M).

The team also administered S63845 (at 25 mg/kg) to mice with MM. Seven of 8 mice had complete regression at 100 days after treatment.

Lymphoma

The investigators tested S63845 in 11 cell lines representative of human lymphomas. Five were highly sensitive to the compound (IC₅₀ < 0.1 μ M), 3 were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 3 were insensitive (IC₅₀ > 1 μ M).

The team also tested S63845 in 7 c-MYC-driven human Burkitt lymphoma cell lines and found the compound exhibited “potent cytotoxic activity” in all of them.

The investigators then tested S63845 in a c-MYC-driven mouse lymphoma model. They noted that both tumor cells and normal tissues express mouse MCL1 protein in this model.

Treatment with S63845 (25 mg/kg) for 5 consecutive days cured 70% of these mice, and the investigators said there were no evident side effects in normal tissues.

Leukemia

The investigators tested S63845 in 5 chronic myeloid leukemia cell lines, and none of them were sensitive to the compound.

However, the team also tested S63845 in 8 acute myeloid leukemia (AML) cell lines, and all of them were sensitive to the compound (IC₅₀ 4–233 nM).

When S63845 was given to mice with AML (25 mg/kg), 6 of the 8 mice achieved complete remission after 80 days.

The investigators also tested S63845 in 25 freshly derived samples from patients with AML. The team said these samples displayed a wide range of responses to S63845.

The most sensitive samples required 100- to 1000-fold less drug (to induce apoptosis) than the resistant samples or normal CD34+ progenitor cells.

Development/funding

S63845 was discovered through a collaboration between 2 pharmaceutical companies—Servier, which is headquartered in France, and Vernalis (R&D), which is based in the UK.

“[C]linical development of a MCL1 inhibitor should be launched in the near future,” said Olivier Geneste, director of oncology research at Servier.

The current research was supported through a collaboration with Servier and through funding from the National Health and Medical Research Council of Australia, the Leukemia and Lymphoma Society, Cancer Council Victoria, the Kay Kendall Leukemia Fund, Victorian Cancer Agency, Australian Cancer Research Foundation, the Victorian Government Operational Infrastructure Scheme, and the estate of Anthony Redstone.

Burkitt lymphoma

Image by Ed Uthman

A new compound has shown promise for treating hematologic malignancies and other cancers, according to preclinical research published in Nature.

The compound, known as S63845, targets the BCL2 family protein MCL1.

Investigators said their research on S63845 provides the first clear evidence that inhibiting MCL1 is effective in targeting several cancer types, including leukemia, lymphoma, and multiple myeloma (MM).

“MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body,” said study author Guillaume Lessene, PhD, of the Walter and Eliza Hall Institute in Melbourne, Australia.

“Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival.”

About S63845

Dr Lessene and his colleagues said S63845 binds with high affinity to the BH3-binding groove of MCL1. And the compound kills MCL1-dependent cancer cells by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.

In solid tumors, S63845 often wasn’t effective enough on its own. However, when the compound was combined with various kinase inhibitors, it induced a “potent cytotoxic response” in breast cancer, lung cancer, and melanoma cells.

In hematologic malignancies, S63845 proved effective when given alone.

Myeloma

The investigators said 17 of 25 MM cell lines tested were highly sensitive to S63845 (IC₅₀ < 0.1 μ M), 6 cell lines were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 2 cell lines were insensitive (IC₅₀ > 1 μ M).

The team also administered S63845 (at 25 mg/kg) to mice with MM. Seven of 8 mice had complete regression at 100 days after treatment.

Lymphoma

The investigators tested S63845 in 11 cell lines representative of human lymphomas. Five were highly sensitive to the compound (IC₅₀ < 0.1 μ M), 3 were moderately sensitive (0.1 μ M < IC₅₀ < 1 μ M), and 3 were insensitive (IC₅₀ > 1 μ M).

The team also tested S63845 in 7 c-MYC-driven human Burkitt lymphoma cell lines and found the compound exhibited “potent cytotoxic activity” in all of them.

The investigators then tested S63845 in a c-MYC-driven mouse lymphoma model. They noted that both tumor cells and normal tissues express mouse MCL1 protein in this model.

Treatment with S63845 (25 mg/kg) for 5 consecutive days cured 70% of these mice, and the investigators said there were no evident side effects in normal tissues.

Leukemia

The investigators tested S63845 in 5 chronic myeloid leukemia cell lines, and none of them were sensitive to the compound.

However, the team also tested S63845 in 8 acute myeloid leukemia (AML) cell lines, and all of them were sensitive to the compound (IC₅₀ 4–233 nM).

When S63845 was given to mice with AML (25 mg/kg), 6 of the 8 mice achieved complete remission after 80 days.

The investigators also tested S63845 in 25 freshly derived samples from patients with AML. The team said these samples displayed a wide range of responses to S63845.

The most sensitive samples required 100- to 1000-fold less drug (to induce apoptosis) than the resistant samples or normal CD34+ progenitor cells.

Development/funding

S63845 was discovered through a collaboration between 2 pharmaceutical companies—Servier, which is headquartered in France, and Vernalis (R&D), which is based in the UK.

“[C]linical development of a MCL1 inhibitor should be launched in the near future,” said Olivier Geneste, director of oncology research at Servier.

The current research was supported through a collaboration with Servier and through funding from the National Health and Medical Research Council of Australia, the Leukemia and Lymphoma Society, Cancer Council Victoria, the Kay Kendall Leukemia Fund, Victorian Cancer Agency, Australian Cancer Research Foundation, the Victorian Government Operational Infrastructure Scheme, and the estate of Anthony Redstone.

Iclusig (ponatinib)

Photo from Business Wire

A pair of US legislators are questioning why ARIAD Pharmaceuticals, Inc. has increased the price of its leukemia drug Iclusig (ponatinib) by more than $80,000 over the last several years.

ARIAD raised the price of Iclusig 4 times in 2016. The drug now costs nearly $199,000 a year.

Senator Bernie Sanders (Vermont) and Congressman Elijah Cummings (Maryland) sent a letter to ARIAD last week requesting information about these price increases.

Cummings and Sanders are also investigating whether ARIAD took additional steps to boost profits by discontinuing sales of certain dosages and quantities of Iclusig in order to charge patients and insurers more in exchange for less medicine.

“These outrageous sales tactics indicate that ARIAD is more concerned with its profit than with its patients,” Sanders and Cummings wrote in the letter.

The US Food and Drug Administration (FDA) approved Iclusig in December 2012 to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

In late 2013, the FDA suspended sales and clinical trials of the drug due to reports of serious adverse events.

The FDA allowed ARIAD to resume selling Iclusig in December 2013, but only to CML/ALL patients who cannot tolerate, or whose disease is resistant to, other tyrosine kinase inhibitors.

“Despite this new evidence showing the drug posed a far greater safety risk to patients than was known when the drug came on the market, ARIAD nonetheless raised the price of Iclusig several times over the subsequent 4 years,” Sanders and Cummings wrote.

“In the interest of patients and taxpayers, we are interested in learning more about the impact that the escalating price and restrictions on product availability have had.”

ARIAD has released a statement acknowledging Cummings’ and Sanders’ letter and defending its decisions to increase the price of Iclusig.

The company said it “makes significant investments in research and development (R&D) to advance breakthrough treatments” for patients with rare cancers.

In fact, ARIAD has invested more than $1.3 billion in R&D and accumulated losses of approximately $1.4 billion, which have not been recovered. In 2015, ARIAD generated $119 million in total revenue and invested $171 million in R&D.

The company said it intends to respond to Cummings’ and Sanders’ request for information.

Iclusig (ponatinib)

Photo from Business Wire

A pair of US legislators are questioning why ARIAD Pharmaceuticals, Inc. has increased the price of its leukemia drug Iclusig (ponatinib) by more than $80,000 over the last several years.

ARIAD raised the price of Iclusig 4 times in 2016. The drug now costs nearly $199,000 a year.

Senator Bernie Sanders (Vermont) and Congressman Elijah Cummings (Maryland) sent a letter to ARIAD last week requesting information about these price increases.

Cummings and Sanders are also investigating whether ARIAD took additional steps to boost profits by discontinuing sales of certain dosages and quantities of Iclusig in order to charge patients and insurers more in exchange for less medicine.

“These outrageous sales tactics indicate that ARIAD is more concerned with its profit than with its patients,” Sanders and Cummings wrote in the letter.

The US Food and Drug Administration (FDA) approved Iclusig in December 2012 to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

In late 2013, the FDA suspended sales and clinical trials of the drug due to reports of serious adverse events.

The FDA allowed ARIAD to resume selling Iclusig in December 2013, but only to CML/ALL patients who cannot tolerate, or whose disease is resistant to, other tyrosine kinase inhibitors.

“Despite this new evidence showing the drug posed a far greater safety risk to patients than was known when the drug came on the market, ARIAD nonetheless raised the price of Iclusig several times over the subsequent 4 years,” Sanders and Cummings wrote.

“In the interest of patients and taxpayers, we are interested in learning more about the impact that the escalating price and restrictions on product availability have had.”

ARIAD has released a statement acknowledging Cummings’ and Sanders’ letter and defending its decisions to increase the price of Iclusig.

The company said it “makes significant investments in research and development (R&D) to advance breakthrough treatments” for patients with rare cancers.

In fact, ARIAD has invested more than $1.3 billion in R&D and accumulated losses of approximately $1.4 billion, which have not been recovered. In 2015, ARIAD generated $119 million in total revenue and invested $171 million in R&D.

The company said it intends to respond to Cummings’ and Sanders’ request for information.

Iclusig (ponatinib)

Photo from Business Wire

A pair of US legislators are questioning why ARIAD Pharmaceuticals, Inc. has increased the price of its leukemia drug Iclusig (ponatinib) by more than $80,000 over the last several years.

ARIAD raised the price of Iclusig 4 times in 2016. The drug now costs nearly $199,000 a year.

Senator Bernie Sanders (Vermont) and Congressman Elijah Cummings (Maryland) sent a letter to ARIAD last week requesting information about these price increases.

Cummings and Sanders are also investigating whether ARIAD took additional steps to boost profits by discontinuing sales of certain dosages and quantities of Iclusig in order to charge patients and insurers more in exchange for less medicine.

“These outrageous sales tactics indicate that ARIAD is more concerned with its profit than with its patients,” Sanders and Cummings wrote in the letter.

The US Food and Drug Administration (FDA) approved Iclusig in December 2012 to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

In late 2013, the FDA suspended sales and clinical trials of the drug due to reports of serious adverse events.

The FDA allowed ARIAD to resume selling Iclusig in December 2013, but only to CML/ALL patients who cannot tolerate, or whose disease is resistant to, other tyrosine kinase inhibitors.

“Despite this new evidence showing the drug posed a far greater safety risk to patients than was known when the drug came on the market, ARIAD nonetheless raised the price of Iclusig several times over the subsequent 4 years,” Sanders and Cummings wrote.

“In the interest of patients and taxpayers, we are interested in learning more about the impact that the escalating price and restrictions on product availability have had.”

ARIAD has released a statement acknowledging Cummings’ and Sanders’ letter and defending its decisions to increase the price of Iclusig.

The company said it “makes significant investments in research and development (R&D) to advance breakthrough treatments” for patients with rare cancers.

In fact, ARIAD has invested more than $1.3 billion in R&D and accumulated losses of approximately $1.4 billion, which have not been recovered. In 2015, ARIAD generated $119 million in total revenue and invested $171 million in R&D.

The company said it intends to respond to Cummings’ and Sanders’ request for information.