CML

Prescription medications

Photo courtesy of CDC

New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).

The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.

“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.

“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”

Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.

The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.

In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.

The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.

The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.

“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”

The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.

“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.

Prescription medications

Photo courtesy of CDC

New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).

The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.

“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.

“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”

Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.

The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.

In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.

The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.

The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.

“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”

The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.

“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.

Prescription medications

Photo courtesy of CDC

New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).

The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.

“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.

“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”

Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.

The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.

In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.

The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.

The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.

“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”

The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.

“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

Patient consults pharmacist

Credit: Rhoda Baer

The European Commission (EC) has concluded that ponatinib (Iclusig) should continue to be prescribed in accordance with its already approved indications.

After trial results suggested the drug poses an increased risk of thrombotic events, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) conducted a review of available ponatinib data.

Results of that review suggested the benefits of ponatinib outweigh the risks. So the committee said the drug should be prescribed as indicated.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently endorsed this recommendation, and, now, the EC has followed suit. The EC’s decision is legally binding.

Ponatinib is approved in the European Union to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

In October 2013, extended follow-up data from the PACE trial revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.

Soon after, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events.

The EMA also revised its recommendations for ponatinib—discouraging use of the drug in certain patients, providing advice for managing comorbidities, and suggesting patient monitoring—but kept the drug on the market.

In October 2014, the PRAC concluded its 11-month review of ponatinib data, confirming that the benefit-risk profile of the drug was favorable in its approved indications and recommending that the indications remain unchanged.

However, the PRAC also said the risk of vascular occlusive events with ponatinib is likely dose-related. So the committee recommended that healthcare professionals monitor ponatinib-treated patients and consider dose reductions or discontinuing the drug in certain patients.

The CHMP endorsed these recommendations, and, now, the EC has as well. This is a legally binding decision for ponatinib to continue to be prescribed in Europe in accordance with its already approved indications.

Ponatinib is being developed by ARIAD Pharmaceuticals, Inc.

Patient consults pharmacist

Credit: Rhoda Baer

The European Commission (EC) has concluded that ponatinib (Iclusig) should continue to be prescribed in accordance with its already approved indications.

After trial results suggested the drug poses an increased risk of thrombotic events, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) conducted a review of available ponatinib data.

Results of that review suggested the benefits of ponatinib outweigh the risks. So the committee said the drug should be prescribed as indicated.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently endorsed this recommendation, and, now, the EC has followed suit. The EC’s decision is legally binding.

Ponatinib is approved in the European Union to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

In October 2013, extended follow-up data from the PACE trial revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.

Soon after, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events.

The EMA also revised its recommendations for ponatinib—discouraging use of the drug in certain patients, providing advice for managing comorbidities, and suggesting patient monitoring—but kept the drug on the market.

In October 2014, the PRAC concluded its 11-month review of ponatinib data, confirming that the benefit-risk profile of the drug was favorable in its approved indications and recommending that the indications remain unchanged.

However, the PRAC also said the risk of vascular occlusive events with ponatinib is likely dose-related. So the committee recommended that healthcare professionals monitor ponatinib-treated patients and consider dose reductions or discontinuing the drug in certain patients.

The CHMP endorsed these recommendations, and, now, the EC has as well. This is a legally binding decision for ponatinib to continue to be prescribed in Europe in accordance with its already approved indications.

Ponatinib is being developed by ARIAD Pharmaceuticals, Inc.

Patient consults pharmacist

Credit: Rhoda Baer

The European Commission (EC) has concluded that ponatinib (Iclusig) should continue to be prescribed in accordance with its already approved indications.

After trial results suggested the drug poses an increased risk of thrombotic events, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) conducted a review of available ponatinib data.

Results of that review suggested the benefits of ponatinib outweigh the risks. So the committee said the drug should be prescribed as indicated.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently endorsed this recommendation, and, now, the EC has followed suit. The EC’s decision is legally binding.

Ponatinib is approved in the European Union to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

In October 2013, extended follow-up data from the PACE trial revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.

Soon after, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events.

The EMA also revised its recommendations for ponatinib—discouraging use of the drug in certain patients, providing advice for managing comorbidities, and suggesting patient monitoring—but kept the drug on the market.

In October 2014, the PRAC concluded its 11-month review of ponatinib data, confirming that the benefit-risk profile of the drug was favorable in its approved indications and recommending that the indications remain unchanged.

However, the PRAC also said the risk of vascular occlusive events with ponatinib is likely dose-related. So the committee recommended that healthcare professionals monitor ponatinib-treated patients and consider dose reductions or discontinuing the drug in certain patients.

The CHMP endorsed these recommendations, and, now, the EC has as well. This is a legally binding decision for ponatinib to continue to be prescribed in Europe in accordance with its already approved indications.

Ponatinib is being developed by ARIAD Pharmaceuticals, Inc.

Prescription medications

Credit: Steven Harbour

The National Health Service (NHS) has increased the budget for England’s Cancer Drugs Fund (CDF) and  added a new drug to treat 2 hematologic malignancies, but 5 other blood cancer drugs will be removed from the fund in March.

The budget for the CDF will grow from £200 million in 2013/14 to £280 million in 2014/15.

However, 16 drugs (for 25 different indications) will no longer be offered through the fund as of March 12, 2015.

Still, the NHS said it has taken steps to ensure patients can receive appropriate treatment.

Review leads to cuts

A national panel of oncologists, pharmacists, and patient representatives independently reviewed the drug indications currently available through the CDF, plus new applications.

They evaluated the clinical benefit, survival, quality of life, toxicity, and safety associated with each treatment, as well as the level of unmet need and the median cost per patient. In cases where the high cost of a drug would lead to its exclusion from CDF, manufacturers were given an opportunity to reduce prices.

The result of the review is that 59 of the 84 most effective currently approved indications of drugs will rollover into the CDF next year, creating room for new drug indications that will be funded for the first time.

These are panitumumab for bowel cancer, ibrutinib for mantle cell lymphoma, and ibrutinib for chronic lymphocytic leukemia.

However, 16 drugs, including 5 blood cancer drugs—bendamustine, bortezomib, bosutinib, dasatinib, and ofatumumab—will no longer be offered through the CDF.

Following these changes, the NHS will put 4 measures in place to ensure patients can receive appropriate treatment. First, any patient currently receiving a drug through the CDF will continue to receive it, regardless of whether it remains in the CDF.

Second, drugs that are the only therapy for the cancer in question will remain available through the CDF. Third, if the CDF panel removes a drug for a particular indication, some patients may instead be able to receive it in another line of therapy or receive an alternative CDF-approved drug.

And finally, clinicians can apply for their patient to receive a drug not available through the CDF on an exceptional basis.

Cuts to blood cancer drugs

The full list of cuts to the CDF is available on the NHS website, but the following list includes all drugs for hematologic malignancies that will no longer be available. These drugs will still be available for other indications, however.

1. Bendamustine for the treatment of low-grade lymphoma that is refractory to rituximab alone or in combination.
2. Bortezomib for the treatment of:

   • relapsed/refractory mantle cell lymphoma after 1 or more prior chemotherapies or stem cell transplant
   • relapsed multiple myeloma patients with a previous partial response or complete response of 6 months or more with bortezomib
   • relapsed Waldenstrom’s macroglobulinemia patients who received previous treatment with alkylating agents and purine analogues.

3. Bosutinib for the treatment of:

   • blast crisis chronic myeloid leukemia (CML) that is refractory to nilotinib or dasatinib if dasatinib was accessed via a clinical trial or via its current approved CDF indication
   • blast crisis CML where there is treatment intolerance, specifically, significant intolerance to dasatinib (grade 3 or 4 adverse events) if dasatinib was accessed via its current approved CDF indication.

4. Dasatinib for the treatment of lymphoid, blast crisis CML that is refractory to, significantly intolerant of, or resistant to prior therapy including imatinib (grade 3 or 4 adverse events); also when used as the 2nd- or 3rd-line treatment.
5. Ofatumumab for the treatment of CML as the 2nd- or 3rd-line indication and if the patient is refractory to treatment with fludarabine in combination and/or alemtuzumab or if treatment with fludarabine in combination and/or alemtuzumab is contraindicated.

More about the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England said it is working with cancer charities, the pharmaceutical industry, and NICE to create a sustainable model for the commissioning of chemotherapy. The agency has also updated its procedures for evaluating drugs in the CDF, in an effort to ensure sustainability.

In addition, NHS England has set up an appeals process by which pharmaceutical companies can challenge the decision-making process.

And a newly assembled national taskforce, headed by Harpal Kumar, chief executive of Cancer Research UK, is set to produce a refreshed, 5-year cancer plan for the NHS.

Prescription medications

Credit: Steven Harbour

The National Health Service (NHS) has increased the budget for England’s Cancer Drugs Fund (CDF) and  added a new drug to treat 2 hematologic malignancies, but 5 other blood cancer drugs will be removed from the fund in March.

The budget for the CDF will grow from £200 million in 2013/14 to £280 million in 2014/15.

However, 16 drugs (for 25 different indications) will no longer be offered through the fund as of March 12, 2015.

Still, the NHS said it has taken steps to ensure patients can receive appropriate treatment.

Review leads to cuts

A national panel of oncologists, pharmacists, and patient representatives independently reviewed the drug indications currently available through the CDF, plus new applications.

They evaluated the clinical benefit, survival, quality of life, toxicity, and safety associated with each treatment, as well as the level of unmet need and the median cost per patient. In cases where the high cost of a drug would lead to its exclusion from CDF, manufacturers were given an opportunity to reduce prices.

The result of the review is that 59 of the 84 most effective currently approved indications of drugs will rollover into the CDF next year, creating room for new drug indications that will be funded for the first time.

These are panitumumab for bowel cancer, ibrutinib for mantle cell lymphoma, and ibrutinib for chronic lymphocytic leukemia.

However, 16 drugs, including 5 blood cancer drugs—bendamustine, bortezomib, bosutinib, dasatinib, and ofatumumab—will no longer be offered through the CDF.

Following these changes, the NHS will put 4 measures in place to ensure patients can receive appropriate treatment. First, any patient currently receiving a drug through the CDF will continue to receive it, regardless of whether it remains in the CDF.

Second, drugs that are the only therapy for the cancer in question will remain available through the CDF. Third, if the CDF panel removes a drug for a particular indication, some patients may instead be able to receive it in another line of therapy or receive an alternative CDF-approved drug.

And finally, clinicians can apply for their patient to receive a drug not available through the CDF on an exceptional basis.

Cuts to blood cancer drugs

The full list of cuts to the CDF is available on the NHS website, but the following list includes all drugs for hematologic malignancies that will no longer be available. These drugs will still be available for other indications, however.

1. Bendamustine for the treatment of low-grade lymphoma that is refractory to rituximab alone or in combination.
2. Bortezomib for the treatment of:

   • relapsed/refractory mantle cell lymphoma after 1 or more prior chemotherapies or stem cell transplant
   • relapsed multiple myeloma patients with a previous partial response or complete response of 6 months or more with bortezomib
   • relapsed Waldenstrom’s macroglobulinemia patients who received previous treatment with alkylating agents and purine analogues.

3. Bosutinib for the treatment of:

   • blast crisis chronic myeloid leukemia (CML) that is refractory to nilotinib or dasatinib if dasatinib was accessed via a clinical trial or via its current approved CDF indication
   • blast crisis CML where there is treatment intolerance, specifically, significant intolerance to dasatinib (grade 3 or 4 adverse events) if dasatinib was accessed via its current approved CDF indication.

4. Dasatinib for the treatment of lymphoid, blast crisis CML that is refractory to, significantly intolerant of, or resistant to prior therapy including imatinib (grade 3 or 4 adverse events); also when used as the 2nd- or 3rd-line treatment.
5. Ofatumumab for the treatment of CML as the 2nd- or 3rd-line indication and if the patient is refractory to treatment with fludarabine in combination and/or alemtuzumab or if treatment with fludarabine in combination and/or alemtuzumab is contraindicated.

More about the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England said it is working with cancer charities, the pharmaceutical industry, and NICE to create a sustainable model for the commissioning of chemotherapy. The agency has also updated its procedures for evaluating drugs in the CDF, in an effort to ensure sustainability.

In addition, NHS England has set up an appeals process by which pharmaceutical companies can challenge the decision-making process.

And a newly assembled national taskforce, headed by Harpal Kumar, chief executive of Cancer Research UK, is set to produce a refreshed, 5-year cancer plan for the NHS.

Prescription medications

Credit: Steven Harbour

The National Health Service (NHS) has increased the budget for England’s Cancer Drugs Fund (CDF) and  added a new drug to treat 2 hematologic malignancies, but 5 other blood cancer drugs will be removed from the fund in March.

The budget for the CDF will grow from £200 million in 2013/14 to £280 million in 2014/15.

However, 16 drugs (for 25 different indications) will no longer be offered through the fund as of March 12, 2015.

Still, the NHS said it has taken steps to ensure patients can receive appropriate treatment.

Review leads to cuts

A national panel of oncologists, pharmacists, and patient representatives independently reviewed the drug indications currently available through the CDF, plus new applications.

They evaluated the clinical benefit, survival, quality of life, toxicity, and safety associated with each treatment, as well as the level of unmet need and the median cost per patient. In cases where the high cost of a drug would lead to its exclusion from CDF, manufacturers were given an opportunity to reduce prices.

The result of the review is that 59 of the 84 most effective currently approved indications of drugs will rollover into the CDF next year, creating room for new drug indications that will be funded for the first time.

These are panitumumab for bowel cancer, ibrutinib for mantle cell lymphoma, and ibrutinib for chronic lymphocytic leukemia.

However, 16 drugs, including 5 blood cancer drugs—bendamustine, bortezomib, bosutinib, dasatinib, and ofatumumab—will no longer be offered through the CDF.

Following these changes, the NHS will put 4 measures in place to ensure patients can receive appropriate treatment. First, any patient currently receiving a drug through the CDF will continue to receive it, regardless of whether it remains in the CDF.

Second, drugs that are the only therapy for the cancer in question will remain available through the CDF. Third, if the CDF panel removes a drug for a particular indication, some patients may instead be able to receive it in another line of therapy or receive an alternative CDF-approved drug.

And finally, clinicians can apply for their patient to receive a drug not available through the CDF on an exceptional basis.

Cuts to blood cancer drugs

The full list of cuts to the CDF is available on the NHS website, but the following list includes all drugs for hematologic malignancies that will no longer be available. These drugs will still be available for other indications, however.

1. Bendamustine for the treatment of low-grade lymphoma that is refractory to rituximab alone or in combination.
2. Bortezomib for the treatment of:

   • relapsed/refractory mantle cell lymphoma after 1 or more prior chemotherapies or stem cell transplant
   • relapsed multiple myeloma patients with a previous partial response or complete response of 6 months or more with bortezomib
   • relapsed Waldenstrom’s macroglobulinemia patients who received previous treatment with alkylating agents and purine analogues.

3. Bosutinib for the treatment of:

   • blast crisis chronic myeloid leukemia (CML) that is refractory to nilotinib or dasatinib if dasatinib was accessed via a clinical trial or via its current approved CDF indication
   • blast crisis CML where there is treatment intolerance, specifically, significant intolerance to dasatinib (grade 3 or 4 adverse events) if dasatinib was accessed via its current approved CDF indication.

4. Dasatinib for the treatment of lymphoid, blast crisis CML that is refractory to, significantly intolerant of, or resistant to prior therapy including imatinib (grade 3 or 4 adverse events); also when used as the 2nd- or 3rd-line treatment.
5. Ofatumumab for the treatment of CML as the 2nd- or 3rd-line indication and if the patient is refractory to treatment with fludarabine in combination and/or alemtuzumab or if treatment with fludarabine in combination and/or alemtuzumab is contraindicated.

More about the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England said it is working with cancer charities, the pharmaceutical industry, and NICE to create a sustainable model for the commissioning of chemotherapy. The agency has also updated its procedures for evaluating drugs in the CDF, in an effort to ensure sustainability.

In addition, NHS England has set up an appeals process by which pharmaceutical companies can challenge the decision-making process.

And a newly assembled national taskforce, headed by Harpal Kumar, chief executive of Cancer Research UK, is set to produce a refreshed, 5-year cancer plan for the NHS.

Chronic myeloid leukemia cells

PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.

Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.

The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.

The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).

Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.

But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.

The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.

They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.

Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.

By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.

The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.

They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.

They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.

Chronic myeloid leukemia cells

PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.

Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.

The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.

The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).

Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.

But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.

The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.

They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.

Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.

By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.

The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.

They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.

They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.

Chronic myeloid leukemia cells

PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.

Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.

The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.

The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).

Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.

But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.

The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.

They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.

Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.

By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.

The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.

They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.

They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.

CML cells

Credit: UCSD School of Medicine

By analyzing structural changes that occur during Abl kinase activation, researchers have gained new insight into this process.

The team discovered a mechanism that links the allosteric regulation of the SH2 domain to two critical phosphorylation events.

As allosteric SH2-kinase domain interactions have proven essential for leukemogenesis caused by Bcr-Abl, the researchers believe this finding has implications for treating chronic myeloid leukemia (CML).

Oliver Hantschel, PhD, of the École polytechnique fédérale de Lausanne (EPFL) in Lausanne, Switzerland, and his colleagues described this work in Nature Communications.

The team made small, strategic mutations to Abl kinase that caused its 3D structure to change. Then, they tested each mutant version of the enzyme to see if its function would change.

The researchers built on previous studies showing that Abl kinase is indirectly controlled by the SH2 region. Normally, the SH2 region regulates the activation loop by opening and closing it. But under the Philadelphia chromosome translocation, that regulation is lost.

The team discovered that when the Philadelphia mutation takes effect, the SH2 region changes the Abl activation loop to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker.

This discovery provides the first-ever picture of the molecular events surrounding the hyperactivity of Abl kinase, the researchers said.

They also found that by disrupting the SH2-kinase interaction, it’s possible to modulate the activity of Abl kinase, which could potentially stop the growth of leukemia.

Since the SH2 region is common to other kinases, the researchers think it’s likely the effect could extend to malignancies other than CML as well, particularly those characterized by abnormal kinase activity.

Finally, the team expects this approach could overcome the problem of drug resistance in CML, as it might offer an alternative way to inhibit Abl kinase, and mutations of rapidly growing cancer cells may be less likely to occur.

CML cells

Credit: UCSD School of Medicine

By analyzing structural changes that occur during Abl kinase activation, researchers have gained new insight into this process.

The team discovered a mechanism that links the allosteric regulation of the SH2 domain to two critical phosphorylation events.

As allosteric SH2-kinase domain interactions have proven essential for leukemogenesis caused by Bcr-Abl, the researchers believe this finding has implications for treating chronic myeloid leukemia (CML).

Oliver Hantschel, PhD, of the École polytechnique fédérale de Lausanne (EPFL) in Lausanne, Switzerland, and his colleagues described this work in Nature Communications.

The team made small, strategic mutations to Abl kinase that caused its 3D structure to change. Then, they tested each mutant version of the enzyme to see if its function would change.

The researchers built on previous studies showing that Abl kinase is indirectly controlled by the SH2 region. Normally, the SH2 region regulates the activation loop by opening and closing it. But under the Philadelphia chromosome translocation, that regulation is lost.

The team discovered that when the Philadelphia mutation takes effect, the SH2 region changes the Abl activation loop to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker.

This discovery provides the first-ever picture of the molecular events surrounding the hyperactivity of Abl kinase, the researchers said.

They also found that by disrupting the SH2-kinase interaction, it’s possible to modulate the activity of Abl kinase, which could potentially stop the growth of leukemia.

Since the SH2 region is common to other kinases, the researchers think it’s likely the effect could extend to malignancies other than CML as well, particularly those characterized by abnormal kinase activity.

Finally, the team expects this approach could overcome the problem of drug resistance in CML, as it might offer an alternative way to inhibit Abl kinase, and mutations of rapidly growing cancer cells may be less likely to occur.

CML cells

Credit: UCSD School of Medicine

By analyzing structural changes that occur during Abl kinase activation, researchers have gained new insight into this process.

The team discovered a mechanism that links the allosteric regulation of the SH2 domain to two critical phosphorylation events.

As allosteric SH2-kinase domain interactions have proven essential for leukemogenesis caused by Bcr-Abl, the researchers believe this finding has implications for treating chronic myeloid leukemia (CML).

Oliver Hantschel, PhD, of the École polytechnique fédérale de Lausanne (EPFL) in Lausanne, Switzerland, and his colleagues described this work in Nature Communications.

The team made small, strategic mutations to Abl kinase that caused its 3D structure to change. Then, they tested each mutant version of the enzyme to see if its function would change.

The researchers built on previous studies showing that Abl kinase is indirectly controlled by the SH2 region. Normally, the SH2 region regulates the activation loop by opening and closing it. But under the Philadelphia chromosome translocation, that regulation is lost.

The team discovered that when the Philadelphia mutation takes effect, the SH2 region changes the Abl activation loop to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker.

This discovery provides the first-ever picture of the molecular events surrounding the hyperactivity of Abl kinase, the researchers said.

They also found that by disrupting the SH2-kinase interaction, it’s possible to modulate the activity of Abl kinase, which could potentially stop the growth of leukemia.

Since the SH2 region is common to other kinases, the researchers think it’s likely the effect could extend to malignancies other than CML as well, particularly those characterized by abnormal kinase activity.

Finally, the team expects this approach could overcome the problem of drug resistance in CML, as it might offer an alternative way to inhibit Abl kinase, and mutations of rapidly growing cancer cells may be less likely to occur.

Scientist at a computer

Credit: Darren Baker

A handful of newly identified compounds may be able to treat chronic myelogenous leukemia (CML) more effectively than the tyrosine kinase inhibitors (TKIs) currently on the market, new research suggests.

Investigators identified 7 molecules that exhibited the potential to be more potent than approved TKIs.

Experiments suggested that 5 of the compounds—DB07107, DB06977, ST013616, DB04200, and ST007180—were more effective at inhibiting T315I-mutant BCR-ABL than wild-type BCR-ABL.

And 2 of them—ST019342 and DB01172—were effective only against mutant BCR-ABL.

Hemanth Naick Banavath, a PhD student at Pondicherry University-India, and his colleagues detailed these results in Nature: Scientific Reports.

To identify compounds to treat CML, the investigators screened several small molecule databases and docked against wild-type and drug-resistant T315I-mutant BCR-ABL.

The team also docked the TKIs ponatinib, bosutinib, bafetinib, dasatinib, nilotinib, and imatinib.

They identified 7 lead molecules—DB07107, DB06977, ST013616, DB04200, ST007180, ST019342, and DB01172—with better binding affinity and higher binding free energy than the TKIs.

Molecular dynamics simulations showed the dynamic behavior of protein-ligand complexes.

The protein backbone and ligand backbone of DB07107, DB06977, ST013616, DB04200, ST007180, and DB01172 were stable throughout the simulation period.

But the backbone of ST019342 showed anomalous fluctuations, and DB01172 showed instability with wild-type BCR-ABL.

A hydrogen bond analysis revealed that DB01172 has 6 hydrogens on average. However, in wild-type, it has 2 to 3 hydrogens on average. The investigators said this suggests low efficacy toward wild-type BCR-ABL.

Taking these findings together, the team said they cannot recommend ST019342 and DB01172 as potential treatments for CML.

On the other hand, they can endorse DB07107, DB06977, ST013616, DB04200, and ST007180, which showed “remarkable results.”

Scientist at a computer

Credit: Darren Baker

A handful of newly identified compounds may be able to treat chronic myelogenous leukemia (CML) more effectively than the tyrosine kinase inhibitors (TKIs) currently on the market, new research suggests.

Investigators identified 7 molecules that exhibited the potential to be more potent than approved TKIs.

Experiments suggested that 5 of the compounds—DB07107, DB06977, ST013616, DB04200, and ST007180—were more effective at inhibiting T315I-mutant BCR-ABL than wild-type BCR-ABL.

And 2 of them—ST019342 and DB01172—were effective only against mutant BCR-ABL.

Hemanth Naick Banavath, a PhD student at Pondicherry University-India, and his colleagues detailed these results in Nature: Scientific Reports.

To identify compounds to treat CML, the investigators screened several small molecule databases and docked against wild-type and drug-resistant T315I-mutant BCR-ABL.

The team also docked the TKIs ponatinib, bosutinib, bafetinib, dasatinib, nilotinib, and imatinib.

They identified 7 lead molecules—DB07107, DB06977, ST013616, DB04200, ST007180, ST019342, and DB01172—with better binding affinity and higher binding free energy than the TKIs.

Molecular dynamics simulations showed the dynamic behavior of protein-ligand complexes.

The protein backbone and ligand backbone of DB07107, DB06977, ST013616, DB04200, ST007180, and DB01172 were stable throughout the simulation period.

But the backbone of ST019342 showed anomalous fluctuations, and DB01172 showed instability with wild-type BCR-ABL.

A hydrogen bond analysis revealed that DB01172 has 6 hydrogens on average. However, in wild-type, it has 2 to 3 hydrogens on average. The investigators said this suggests low efficacy toward wild-type BCR-ABL.

Taking these findings together, the team said they cannot recommend ST019342 and DB01172 as potential treatments for CML.

On the other hand, they can endorse DB07107, DB06977, ST013616, DB04200, and ST007180, which showed “remarkable results.”

Scientist at a computer

Credit: Darren Baker

A handful of newly identified compounds may be able to treat chronic myelogenous leukemia (CML) more effectively than the tyrosine kinase inhibitors (TKIs) currently on the market, new research suggests.

Investigators identified 7 molecules that exhibited the potential to be more potent than approved TKIs.

Experiments suggested that 5 of the compounds—DB07107, DB06977, ST013616, DB04200, and ST007180—were more effective at inhibiting T315I-mutant BCR-ABL than wild-type BCR-ABL.

And 2 of them—ST019342 and DB01172—were effective only against mutant BCR-ABL.

Hemanth Naick Banavath, a PhD student at Pondicherry University-India, and his colleagues detailed these results in Nature: Scientific Reports.

To identify compounds to treat CML, the investigators screened several small molecule databases and docked against wild-type and drug-resistant T315I-mutant BCR-ABL.

The team also docked the TKIs ponatinib, bosutinib, bafetinib, dasatinib, nilotinib, and imatinib.

They identified 7 lead molecules—DB07107, DB06977, ST013616, DB04200, ST007180, ST019342, and DB01172—with better binding affinity and higher binding free energy than the TKIs.

Molecular dynamics simulations showed the dynamic behavior of protein-ligand complexes.

The protein backbone and ligand backbone of DB07107, DB06977, ST013616, DB04200, ST007180, and DB01172 were stable throughout the simulation period.

But the backbone of ST019342 showed anomalous fluctuations, and DB01172 showed instability with wild-type BCR-ABL.

A hydrogen bond analysis revealed that DB01172 has 6 hydrogens on average. However, in wild-type, it has 2 to 3 hydrogens on average. The investigators said this suggests low efficacy toward wild-type BCR-ABL.

Taking these findings together, the team said they cannot recommend ST019342 and DB01172 as potential treatments for CML.

On the other hand, they can endorse DB07107, DB06977, ST013616, DB04200, and ST007180, which showed “remarkable results.”

The development of vitiligo or alopecia areata is not common in patients with chronic graft-versus-host disease, but it is significantly more likely to occur when the donor was female, especially when the recipient was male, according to a report published online Sept. 10 in JAMA Dermatology.

Fifteen case reports and small series in the literature have reported the development of vitiligo or alopecia areata after allogeneic hematopoietic stem cell transplantation, most often among patients who first developed chronic graft-versus-host disease (GVHD) after the procedure. To further explore the frequency of these two skin autoimmune manifestations in GVHD and to identify associated risk factors, researchers performed a retrospective cross-sectional analysis involving 282 adult and pediatric patients referred to the National Institutes of Health Clinical Center for GVHD in 2004-2013.

Courtesy Wikimedia Commons/Grook Da Oger/Creative Commons License

They identified 15 GVHD patients with vitiligo (4.9%) and 2 with alopecia areata (0.7%); one of these patients had both skin disorders. Most of the 15 patients had undergone stem-cell transplantation to treat chronic myelogenous leukemia (CML) (5 patients) or acute leukemia or myelodysplastic syndrome (5 patients), and most had had a human leukocyte antigen–identical donor. Twelve of the 15 developed the skin disorder after having GVHD for more than 1 year, said Rena C. Zuo of the National Cancer Institute’s dermatology branch and her associates.

"Notably, CML accounts for only about 300 of 7,892 (3.8%) allogeneic hematopoietic stem-cell transplantations per year in the United States, a relative minority among indicated diseases," they said.

In what they described as the first study to identify an association between donor/recipient sex mismatch and the development of concomitant autoimmunity in patients with chronic GVHD, the investigators found that 14 of the 15 patients who developed vitiligo or alopecia areata had female donors, 2 of whom had previously given birth; the gender of the donor in the 15th case was unknown. Nine of these 14 recipients were male, "resulting in a female-to-male sex mismatch in [at least] 64% of cases," Ms. Zuo and her colleagues said (JAMA Dermatol. 2014 Sept. 10 [doi:10.1001/jamadermatol.2014.1550]).

Both parous female donors and donor-recipient sex mismatch are known risk factors for GVHD. The risk of autoimmunity in female-to-male transplants "may reflect the activity of skin-homing donor T cells specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes, a mechanism previously implicated in both GVHD and graft-versus-tumor responses," the investigators added.

This study was supported by the National Institutes of Health and the National Cancer Institute. Ms. Zuo and her associates reported no financial conflicts of interest.

The development of vitiligo or alopecia areata is not common in patients with chronic graft-versus-host disease, but it is significantly more likely to occur when the donor was female, especially when the recipient was male, according to a report published online Sept. 10 in JAMA Dermatology.

Fifteen case reports and small series in the literature have reported the development of vitiligo or alopecia areata after allogeneic hematopoietic stem cell transplantation, most often among patients who first developed chronic graft-versus-host disease (GVHD) after the procedure. To further explore the frequency of these two skin autoimmune manifestations in GVHD and to identify associated risk factors, researchers performed a retrospective cross-sectional analysis involving 282 adult and pediatric patients referred to the National Institutes of Health Clinical Center for GVHD in 2004-2013.

Courtesy Wikimedia Commons/Grook Da Oger/Creative Commons License

They identified 15 GVHD patients with vitiligo (4.9%) and 2 with alopecia areata (0.7%); one of these patients had both skin disorders. Most of the 15 patients had undergone stem-cell transplantation to treat chronic myelogenous leukemia (CML) (5 patients) or acute leukemia or myelodysplastic syndrome (5 patients), and most had had a human leukocyte antigen–identical donor. Twelve of the 15 developed the skin disorder after having GVHD for more than 1 year, said Rena C. Zuo of the National Cancer Institute’s dermatology branch and her associates.

"Notably, CML accounts for only about 300 of 7,892 (3.8%) allogeneic hematopoietic stem-cell transplantations per year in the United States, a relative minority among indicated diseases," they said.

In what they described as the first study to identify an association between donor/recipient sex mismatch and the development of concomitant autoimmunity in patients with chronic GVHD, the investigators found that 14 of the 15 patients who developed vitiligo or alopecia areata had female donors, 2 of whom had previously given birth; the gender of the donor in the 15th case was unknown. Nine of these 14 recipients were male, "resulting in a female-to-male sex mismatch in [at least] 64% of cases," Ms. Zuo and her colleagues said (JAMA Dermatol. 2014 Sept. 10 [doi:10.1001/jamadermatol.2014.1550]).

Both parous female donors and donor-recipient sex mismatch are known risk factors for GVHD. The risk of autoimmunity in female-to-male transplants "may reflect the activity of skin-homing donor T cells specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes, a mechanism previously implicated in both GVHD and graft-versus-tumor responses," the investigators added.

This study was supported by the National Institutes of Health and the National Cancer Institute. Ms. Zuo and her associates reported no financial conflicts of interest.

The development of vitiligo or alopecia areata is not common in patients with chronic graft-versus-host disease, but it is significantly more likely to occur when the donor was female, especially when the recipient was male, according to a report published online Sept. 10 in JAMA Dermatology.

Fifteen case reports and small series in the literature have reported the development of vitiligo or alopecia areata after allogeneic hematopoietic stem cell transplantation, most often among patients who first developed chronic graft-versus-host disease (GVHD) after the procedure. To further explore the frequency of these two skin autoimmune manifestations in GVHD and to identify associated risk factors, researchers performed a retrospective cross-sectional analysis involving 282 adult and pediatric patients referred to the National Institutes of Health Clinical Center for GVHD in 2004-2013.

Courtesy Wikimedia Commons/Grook Da Oger/Creative Commons License

They identified 15 GVHD patients with vitiligo (4.9%) and 2 with alopecia areata (0.7%); one of these patients had both skin disorders. Most of the 15 patients had undergone stem-cell transplantation to treat chronic myelogenous leukemia (CML) (5 patients) or acute leukemia or myelodysplastic syndrome (5 patients), and most had had a human leukocyte antigen–identical donor. Twelve of the 15 developed the skin disorder after having GVHD for more than 1 year, said Rena C. Zuo of the National Cancer Institute’s dermatology branch and her associates.

"Notably, CML accounts for only about 300 of 7,892 (3.8%) allogeneic hematopoietic stem-cell transplantations per year in the United States, a relative minority among indicated diseases," they said.

In what they described as the first study to identify an association between donor/recipient sex mismatch and the development of concomitant autoimmunity in patients with chronic GVHD, the investigators found that 14 of the 15 patients who developed vitiligo or alopecia areata had female donors, 2 of whom had previously given birth; the gender of the donor in the 15th case was unknown. Nine of these 14 recipients were male, "resulting in a female-to-male sex mismatch in [at least] 64% of cases," Ms. Zuo and her colleagues said (JAMA Dermatol. 2014 Sept. 10 [doi:10.1001/jamadermatol.2014.1550]).

Both parous female donors and donor-recipient sex mismatch are known risk factors for GVHD. The risk of autoimmunity in female-to-male transplants "may reflect the activity of skin-homing donor T cells specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes, a mechanism previously implicated in both GVHD and graft-versus-tumor responses," the investigators added.

This study was supported by the National Institutes of Health and the National Cancer Institute. Ms. Zuo and her associates reported no financial conflicts of interest.

Lab mouse

A new study helps explain why some chronic myeloid leukemia (CML) patients develop resistance to imatinib despite the absence of BCR-ABL mutations.

Researchers discovered that a signaling pathway associated with cell division and growth acts as an alternative survival signal underlying imatinib resistance.

But blocking this pathway with an inhibitor known as trametinib can prevent resistance to imatinib and increase survival in mice.

The researchers recounted these discoveries in Science Translational Medicine.

Michael R. Green, MD, PhD, of the University of Massachusetts Medical School in Worcester, and his colleagues began this research with a large-scale RNA interference screen. This revealed a set of genes that promote imatinib sensitivity.

The team then set out to identify the regulatory pathways through which these genes promote imatinib sensitivity. They found that knocking down the genes in BCR-ABL+ cells results in sustained RAF/MEK/ERK signaling after treatment with imatinib.

Further investigation revealed it is PRKCH, which encodes the protein kinase C family member PKCη, that increases RAF/MEK/ERK signaling through phosphorylation and activation of CRAF.

Dr Green and his colleagues also found that PRKCH is upregulated in CML cell lines and patient samples that exhibit BCR-ABL-independent imatinib resistance. Experiments in mice revealed that PRKCH modulates the proliferation of BCR-ABL+ cells, CML progression, and imatinib sensitivity.

Furthermore, imatinib-resistant murine and human CML stem cells contained high levels of PRKCH. And experiments confirmed that high PRKCH expression contributed to the imatinib resistance observed in these cells.

Fortunately, the researchers discovered that combining imatinib with the MEK inhibitor trametinib can overcome BCR-ABL-independent imatinib resistance in CML cells. The combination also prolonged survival in mouse models of imatinib-resistant CML.

Dr Green and his colleagues said these results reveal a mechanism of BCR-ABL-independent imatinib resistance that can be targeted with therapy. And, as treatment with trametinib and imatinib kills CML stem cells but spares normal hematopoietic stem cells, it may be a feasible treatment option for CML patients.

Lab mouse

A new study helps explain why some chronic myeloid leukemia (CML) patients develop resistance to imatinib despite the absence of BCR-ABL mutations.

Researchers discovered that a signaling pathway associated with cell division and growth acts as an alternative survival signal underlying imatinib resistance.

But blocking this pathway with an inhibitor known as trametinib can prevent resistance to imatinib and increase survival in mice.

The researchers recounted these discoveries in Science Translational Medicine.

Michael R. Green, MD, PhD, of the University of Massachusetts Medical School in Worcester, and his colleagues began this research with a large-scale RNA interference screen. This revealed a set of genes that promote imatinib sensitivity.

The team then set out to identify the regulatory pathways through which these genes promote imatinib sensitivity. They found that knocking down the genes in BCR-ABL+ cells results in sustained RAF/MEK/ERK signaling after treatment with imatinib.

Further investigation revealed it is PRKCH, which encodes the protein kinase C family member PKCη, that increases RAF/MEK/ERK signaling through phosphorylation and activation of CRAF.

Dr Green and his colleagues also found that PRKCH is upregulated in CML cell lines and patient samples that exhibit BCR-ABL-independent imatinib resistance. Experiments in mice revealed that PRKCH modulates the proliferation of BCR-ABL+ cells, CML progression, and imatinib sensitivity.

Furthermore, imatinib-resistant murine and human CML stem cells contained high levels of PRKCH. And experiments confirmed that high PRKCH expression contributed to the imatinib resistance observed in these cells.

Fortunately, the researchers discovered that combining imatinib with the MEK inhibitor trametinib can overcome BCR-ABL-independent imatinib resistance in CML cells. The combination also prolonged survival in mouse models of imatinib-resistant CML.

Dr Green and his colleagues said these results reveal a mechanism of BCR-ABL-independent imatinib resistance that can be targeted with therapy. And, as treatment with trametinib and imatinib kills CML stem cells but spares normal hematopoietic stem cells, it may be a feasible treatment option for CML patients.

Lab mouse

A new study helps explain why some chronic myeloid leukemia (CML) patients develop resistance to imatinib despite the absence of BCR-ABL mutations.

Researchers discovered that a signaling pathway associated with cell division and growth acts as an alternative survival signal underlying imatinib resistance.

But blocking this pathway with an inhibitor known as trametinib can prevent resistance to imatinib and increase survival in mice.

The researchers recounted these discoveries in Science Translational Medicine.

Michael R. Green, MD, PhD, of the University of Massachusetts Medical School in Worcester, and his colleagues began this research with a large-scale RNA interference screen. This revealed a set of genes that promote imatinib sensitivity.

The team then set out to identify the regulatory pathways through which these genes promote imatinib sensitivity. They found that knocking down the genes in BCR-ABL+ cells results in sustained RAF/MEK/ERK signaling after treatment with imatinib.

Further investigation revealed it is PRKCH, which encodes the protein kinase C family member PKCη, that increases RAF/MEK/ERK signaling through phosphorylation and activation of CRAF.

Dr Green and his colleagues also found that PRKCH is upregulated in CML cell lines and patient samples that exhibit BCR-ABL-independent imatinib resistance. Experiments in mice revealed that PRKCH modulates the proliferation of BCR-ABL+ cells, CML progression, and imatinib sensitivity.

Furthermore, imatinib-resistant murine and human CML stem cells contained high levels of PRKCH. And experiments confirmed that high PRKCH expression contributed to the imatinib resistance observed in these cells.

Fortunately, the researchers discovered that combining imatinib with the MEK inhibitor trametinib can overcome BCR-ABL-independent imatinib resistance in CML cells. The combination also prolonged survival in mouse models of imatinib-resistant CML.

Dr Green and his colleagues said these results reveal a mechanism of BCR-ABL-independent imatinib resistance that can be targeted with therapy. And, as treatment with trametinib and imatinib kills CML stem cells but spares normal hematopoietic stem cells, it may be a feasible treatment option for CML patients.

CML cells

Credit: UC San Diego

In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).

Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.

So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.

The results appear in Cancer Cell.

Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.

The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.

All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.

The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.

“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.

“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.

Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.

The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.

But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.

The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.

So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.

“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”

According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.

“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.

CML cells

Credit: UC San Diego

In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).

Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.

So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.

The results appear in Cancer Cell.

Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.

The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.

All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.

The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.

“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.

“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.

Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.

The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.

But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.

The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.

So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.

“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”

According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.

“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.

CML cells

Credit: UC San Diego

In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).

Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.

So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.

The results appear in Cancer Cell.

Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.

The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.

All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.

The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.

“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.

“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.

Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.

The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.

But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.

The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.

So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.

“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”

According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.

“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.