Myelodysplastic Syndrome

Red and white blood cells

New research suggests that clonality may underlie the cytopenias observed in patients with idiopathic cytopenias of undetermined significance (ICUS).

So researchers say these patients should be classified as having clonal cytopenias of undetermined significance (CCUS).

The team believes that recognition of CCUS as a clinical entity would help identify it as a formally defined diagnostic group and could aid future studies.

“We don’t know to what extent patients who have low blood counts and mutations are at increased risk of developing an overt malignancy,” said Rafael Bejar, MD, PhD, of the UCSD Moores Cancer Center in La Jolla, California.

“We hope that by defining CCUS, future studies will follow these patients to learn what these mutations mean for their future, as their genetically abnormal cells may represent early stages of subsequent blood cancers.”

Dr Bejar and his colleagues defined CCUS in Blood. Their research was funded, in part, by Genoptix Medical Laboratory, and several study authors are employees of Genoptix.

The researchers prospectively examined bone marrow samples from 144 patients with unexplained cytopenias. Seventeen percent of these patients were diagnosed with myelodysplastic syndromes (MDS), 15% with ICUS and some evidence of dysplasia, and 69% with ICUS and no dysplasia.

The team then sequenced patient samples looking for mutations in 22 frequently mutated myeloid malignancy genes. They identified somatic mutations in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients with no dysplasia.

Overall, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis.

To build upon these findings, the researchers performed a retrospective analysis of data from 91 patients with lower-risk MDS and 249 patients with ICUS.

The team identified mutations in 79% of patients with MDS, 45% of patients with ICUS and dysplasia, and 17% of patients with ICUS and no dysplasia.

The researchers said the spectrum of mutated genes was similar among the 3 groups. The exception was SF3B1, which was rarely mutated in patients without dysplasia.

The team added that variant allele fractions were comparable between clonal ICUS (CCUS) and MDS, and the same was true for the patients’ mean age and blood counts. But CCUS was a more frequent diagnosis than MDS.

Dr Bejar and his colleagues said larger, carefully controlled studies will be needed to confirm the findings of this research.

Red and white blood cells

New research suggests that clonality may underlie the cytopenias observed in patients with idiopathic cytopenias of undetermined significance (ICUS).

So researchers say these patients should be classified as having clonal cytopenias of undetermined significance (CCUS).

The team believes that recognition of CCUS as a clinical entity would help identify it as a formally defined diagnostic group and could aid future studies.

“We don’t know to what extent patients who have low blood counts and mutations are at increased risk of developing an overt malignancy,” said Rafael Bejar, MD, PhD, of the UCSD Moores Cancer Center in La Jolla, California.

“We hope that by defining CCUS, future studies will follow these patients to learn what these mutations mean for their future, as their genetically abnormal cells may represent early stages of subsequent blood cancers.”

Dr Bejar and his colleagues defined CCUS in Blood. Their research was funded, in part, by Genoptix Medical Laboratory, and several study authors are employees of Genoptix.

The researchers prospectively examined bone marrow samples from 144 patients with unexplained cytopenias. Seventeen percent of these patients were diagnosed with myelodysplastic syndromes (MDS), 15% with ICUS and some evidence of dysplasia, and 69% with ICUS and no dysplasia.

The team then sequenced patient samples looking for mutations in 22 frequently mutated myeloid malignancy genes. They identified somatic mutations in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients with no dysplasia.

Overall, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis.

To build upon these findings, the researchers performed a retrospective analysis of data from 91 patients with lower-risk MDS and 249 patients with ICUS.

The team identified mutations in 79% of patients with MDS, 45% of patients with ICUS and dysplasia, and 17% of patients with ICUS and no dysplasia.

The researchers said the spectrum of mutated genes was similar among the 3 groups. The exception was SF3B1, which was rarely mutated in patients without dysplasia.

The team added that variant allele fractions were comparable between clonal ICUS (CCUS) and MDS, and the same was true for the patients’ mean age and blood counts. But CCUS was a more frequent diagnosis than MDS.

Dr Bejar and his colleagues said larger, carefully controlled studies will be needed to confirm the findings of this research.

Red and white blood cells

New research suggests that clonality may underlie the cytopenias observed in patients with idiopathic cytopenias of undetermined significance (ICUS).

So researchers say these patients should be classified as having clonal cytopenias of undetermined significance (CCUS).

The team believes that recognition of CCUS as a clinical entity would help identify it as a formally defined diagnostic group and could aid future studies.

“We don’t know to what extent patients who have low blood counts and mutations are at increased risk of developing an overt malignancy,” said Rafael Bejar, MD, PhD, of the UCSD Moores Cancer Center in La Jolla, California.

“We hope that by defining CCUS, future studies will follow these patients to learn what these mutations mean for their future, as their genetically abnormal cells may represent early stages of subsequent blood cancers.”

Dr Bejar and his colleagues defined CCUS in Blood. Their research was funded, in part, by Genoptix Medical Laboratory, and several study authors are employees of Genoptix.

The researchers prospectively examined bone marrow samples from 144 patients with unexplained cytopenias. Seventeen percent of these patients were diagnosed with myelodysplastic syndromes (MDS), 15% with ICUS and some evidence of dysplasia, and 69% with ICUS and no dysplasia.

The team then sequenced patient samples looking for mutations in 22 frequently mutated myeloid malignancy genes. They identified somatic mutations in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients with no dysplasia.

Overall, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis.

To build upon these findings, the researchers performed a retrospective analysis of data from 91 patients with lower-risk MDS and 249 patients with ICUS.

The team identified mutations in 79% of patients with MDS, 45% of patients with ICUS and dysplasia, and 17% of patients with ICUS and no dysplasia.

The researchers said the spectrum of mutated genes was similar among the 3 groups. The exception was SF3B1, which was rarely mutated in patients without dysplasia.

The team added that variant allele fractions were comparable between clonal ICUS (CCUS) and MDS, and the same was true for the patients’ mean age and blood counts. But CCUS was a more frequent diagnosis than MDS.

Dr Bejar and his colleagues said larger, carefully controlled studies will be needed to confirm the findings of this research.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

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 and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

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 and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

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 and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

ALEXANDRIA, VA. – How are mutation analysis gene panels affecting risk stratification and decision making regarding stem cell transplants in myelofibrosis patients? How are the results of the Dynamic International Prognostic Scoring System (DIPSS) and performance status improvements seen with JAK2 inhibitors influencing who is a candidate for transplant and the timing of transplants?

Watch the conversation between Dr. Vikas Gupta of the leukemia and bone marrow transplant programs at the Princess Margaret Cancer Centre, Toronto, and associate professor of medicine at the University of Toronto, and Dr. Rami S. Komrokji of the Moffitt Cancer Center, Tampa, Fla., as they discuss their individual approaches that consider patient wishes and goals, type of donor, and disease risk in their decisions to perform stem cell transplants upfront or to delay them until after JAK2 inhibitor therapy.

Have an insight to share? Post a comment.

[email protected]

ALEXANDRIA, VA. – How are mutation analysis gene panels affecting risk stratification and decision making regarding stem cell transplants in myelofibrosis patients? How are the results of the Dynamic International Prognostic Scoring System (DIPSS) and performance status improvements seen with JAK2 inhibitors influencing who is a candidate for transplant and the timing of transplants?

Watch the conversation between Dr. Vikas Gupta of the leukemia and bone marrow transplant programs at the Princess Margaret Cancer Centre, Toronto, and associate professor of medicine at the University of Toronto, and Dr. Rami S. Komrokji of the Moffitt Cancer Center, Tampa, Fla., as they discuss their individual approaches that consider patient wishes and goals, type of donor, and disease risk in their decisions to perform stem cell transplants upfront or to delay them until after JAK2 inhibitor therapy.

Have an insight to share? Post a comment.

[email protected]

ALEXANDRIA, VA. – How are mutation analysis gene panels affecting risk stratification and decision making regarding stem cell transplants in myelofibrosis patients? How are the results of the Dynamic International Prognostic Scoring System (DIPSS) and performance status improvements seen with JAK2 inhibitors influencing who is a candidate for transplant and the timing of transplants?

Watch the conversation between Dr. Vikas Gupta of the leukemia and bone marrow transplant programs at the Princess Margaret Cancer Centre, Toronto, and associate professor of medicine at the University of Toronto, and Dr. Rami S. Komrokji of the Moffitt Cancer Center, Tampa, Fla., as they discuss their individual approaches that consider patient wishes and goals, type of donor, and disease risk in their decisions to perform stem cell transplants upfront or to delay them until after JAK2 inhibitor therapy.

Have an insight to share? Post a comment.

[email protected]

ALEXANDRIA, VA. – What are the emerging combination therapies for slowing disease progression and improving therapeutic tolerability in myeloproliferative neoplasms and myelodysplastic syndromes?

Join Dr. Jaroslaw Maciejewski, chairman of the department of translational hematology and oncology research at the Taussig Cancer Institute, Cleveland Clinic, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and Dr. Ruben A. Mesa, chair of the Division of Hematology/Oncology, department of internal medicine, Mayo Clinic, Scottsdale, Arizona, for their one-on-one discussion of emerging treatment approaches. Then join the conversation by posting your comments and recommendations for other Heme Themes.

[email protected]

ALEXANDRIA, VA. – What are the emerging combination therapies for slowing disease progression and improving therapeutic tolerability in myeloproliferative neoplasms and myelodysplastic syndromes?

Join Dr. Jaroslaw Maciejewski, chairman of the department of translational hematology and oncology research at the Taussig Cancer Institute, Cleveland Clinic, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and Dr. Ruben A. Mesa, chair of the Division of Hematology/Oncology, department of internal medicine, Mayo Clinic, Scottsdale, Arizona, for their one-on-one discussion of emerging treatment approaches. Then join the conversation by posting your comments and recommendations for other Heme Themes.

[email protected]

ALEXANDRIA, VA. – What are the emerging combination therapies for slowing disease progression and improving therapeutic tolerability in myeloproliferative neoplasms and myelodysplastic syndromes?

Join Dr. Jaroslaw Maciejewski, chairman of the department of translational hematology and oncology research at the Taussig Cancer Institute, Cleveland Clinic, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and Dr. Ruben A. Mesa, chair of the Division of Hematology/Oncology, department of internal medicine, Mayo Clinic, Scottsdale, Arizona, for their one-on-one discussion of emerging treatment approaches. Then join the conversation by posting your comments and recommendations for other Heme Themes.

[email protected]

The telomerase inhibitor imetelstat showed promise against advanced myelofibrosis and essential thrombocythemia in two industry-funded preliminary studies, according to separate reports published online Sept. 3 in the New England Journal of Medicine.

In previous in vitro and animal studies, imetelstat inhibited the proliferation of various types of malignant cells but was not active in normal somatic tissue. Researchers assessed the agent for advanced myelofibrosis in part because, at present, only one available treatment – allogeneic stem-cell transplantation (ASCT) – sometimes induces long-term remission. ASCT carries a relatively high rate of treatment-related death and complications, and is contraindicated in many older patients.

In the first report, researchers conducted a small, single-center cohort study to collect preliminary data on the agent’s efficacy and safety in 33 patients with primary myelofibrosis (18 participants), myelofibrosis that was related to polycythemia (10 participants), or myelofibrosis associated with essential thrombocytopenia (10 participants). Imetelstat was administered in 2-hour intravenous infusions given in 3-week cycles, said Dr. Ayalew Tefferi of the division of hematology, Mayo Clinic, Rochester Minn.

©Ed Uthman/flickr.com

The median duration of treatment was 8.6 months (range, 1.4-21.7 months). Seven patients (21%) had either a complete or partial response; the 4 patients with a complete response had documented complete reversal of bone marrow fibrosis. The time to onset of response was 3.5 months (range, 1.4-7.2 months), and the median duration of response was 18 months (range, 13-20 months).

These remissions “confirm selective anticlonal activity, which has not previously been documented in drug treatment of myelofibrosis,” noted Dr. Tefferi and his associates (N Engl J Med 2015 Sep 3. doi:10.1056/NEJMoa1310523). Three of the seven patients who responded to imetelstat “had been heavily dependent on red-cell transfusions at study entry and became transfusion-independent and sustained a hemoglobin level of more than 10 g/dL for a minimum of 3 months during therapy,” they noted.

In addition, 8 of 10 patients who had marked leukocytosis at baseline had either a complete resolution (3 patients) or a reduction of at least 50% in white-cell counts (5 patients). All 11 participants who had thrombocytosis at baseline had either complete resolution (10 patients) or a reduction in platelet count of at least 50% (1 patient). Of the 27 participants who had leukoerythroblastosis at baseline, 22 showed either complete resolution (13 patients) or a reduction of at least 50% in the percentage of immature myeloid cells and nucleated red cells (9 patients). Also, 17 of the 21 participants who had at least 1% circulating blasts at baseline had either a complete disappearance of circulating blasts (14 patients) or a reduction of at least 50% (3 patients).

The most clinically significant adverse effect of imetelstat, myelosuppression, occurred in 22 patients (67%) and often necessitated dose reductions. Low-grade elevations in liver enzymes also were a concern. One patient died from an intracranial hemorrhage that the treating physician attributed to drug-induced grade 4 thrombocytopenia. Other adverse events that may or may not have been treatment related included fever, epistaxis, bruising, hematoma, lung infection, skin infection, and upper-GI hemorrhage.

These findings not only identify imetelstat as a possible treatment for myelofibrosis, they also suggest that other telomerase-targeting strategies may be beneficial in this disease, Dr. Tefferi and his associates added.

In the second report, researchers performing a phase-II study at seven medical centers in the United States, Germany, and Switzerland found that imetelstat produced rapid and durable hematologic and molecular responses in all 18 patients in their study of essential thrombocythemia refractory to other treatments. This result is particularly encouraging because current standard therapies “induce nonspecific reductions in platelet counts but do not typically eliminate or alter the biologic characteristics of the disease,” said Dr. Gabriela M. Baerlocher of the department of hematology and the Stem Cell Molecular Diagnostics Laboratory, University of Bern, Switzerland.

These study participants had either failed to respond to hydroxyurea, anagrelide, and interferon therapy or were forced to discontinue these agents because of adverse effects. After weekly treatment with imetelstat at one of two doses, 100% of the patients achieved a hematologic response, attaining platelet counts of 250,000-300,000 per cc. Sixteen participants (89%) achieved a complete hematologic response. The median time to complete response was 6.1 weeks, Dr. Baerlocher and her associates said (N Engl J Med. 2015 Sep 3. doi:10.1056/NEJMoa1503479).

After a median follow-up of 17 months on a maintenance dose of imetelstat, 10 patients were still receiving treatment. The median duration of response had not been reached as of press time (range, 5-30 months).

The most important adverse events were neutropenia (15 patients) and abnormal results on liver-function tests (14 patients). The treating physicians attributed 18 adverse events of grade 3 or higher to the study drug, including headache, anemia, and one syncopal episode. Other adverse events included fatigue, nausea, diarrhea, infections, and rash.

The telomerase inhibitor imetelstat showed promise against advanced myelofibrosis and essential thrombocythemia in two industry-funded preliminary studies, according to separate reports published online Sept. 3 in the New England Journal of Medicine.

In previous in vitro and animal studies, imetelstat inhibited the proliferation of various types of malignant cells but was not active in normal somatic tissue. Researchers assessed the agent for advanced myelofibrosis in part because, at present, only one available treatment – allogeneic stem-cell transplantation (ASCT) – sometimes induces long-term remission. ASCT carries a relatively high rate of treatment-related death and complications, and is contraindicated in many older patients.

In the first report, researchers conducted a small, single-center cohort study to collect preliminary data on the agent’s efficacy and safety in 33 patients with primary myelofibrosis (18 participants), myelofibrosis that was related to polycythemia (10 participants), or myelofibrosis associated with essential thrombocytopenia (10 participants). Imetelstat was administered in 2-hour intravenous infusions given in 3-week cycles, said Dr. Ayalew Tefferi of the division of hematology, Mayo Clinic, Rochester Minn.

©Ed Uthman/flickr.com

The median duration of treatment was 8.6 months (range, 1.4-21.7 months). Seven patients (21%) had either a complete or partial response; the 4 patients with a complete response had documented complete reversal of bone marrow fibrosis. The time to onset of response was 3.5 months (range, 1.4-7.2 months), and the median duration of response was 18 months (range, 13-20 months).

These remissions “confirm selective anticlonal activity, which has not previously been documented in drug treatment of myelofibrosis,” noted Dr. Tefferi and his associates (N Engl J Med 2015 Sep 3. doi:10.1056/NEJMoa1310523). Three of the seven patients who responded to imetelstat “had been heavily dependent on red-cell transfusions at study entry and became transfusion-independent and sustained a hemoglobin level of more than 10 g/dL for a minimum of 3 months during therapy,” they noted.

In addition, 8 of 10 patients who had marked leukocytosis at baseline had either a complete resolution (3 patients) or a reduction of at least 50% in white-cell counts (5 patients). All 11 participants who had thrombocytosis at baseline had either complete resolution (10 patients) or a reduction in platelet count of at least 50% (1 patient). Of the 27 participants who had leukoerythroblastosis at baseline, 22 showed either complete resolution (13 patients) or a reduction of at least 50% in the percentage of immature myeloid cells and nucleated red cells (9 patients). Also, 17 of the 21 participants who had at least 1% circulating blasts at baseline had either a complete disappearance of circulating blasts (14 patients) or a reduction of at least 50% (3 patients).

The most clinically significant adverse effect of imetelstat, myelosuppression, occurred in 22 patients (67%) and often necessitated dose reductions. Low-grade elevations in liver enzymes also were a concern. One patient died from an intracranial hemorrhage that the treating physician attributed to drug-induced grade 4 thrombocytopenia. Other adverse events that may or may not have been treatment related included fever, epistaxis, bruising, hematoma, lung infection, skin infection, and upper-GI hemorrhage.

These findings not only identify imetelstat as a possible treatment for myelofibrosis, they also suggest that other telomerase-targeting strategies may be beneficial in this disease, Dr. Tefferi and his associates added.

In the second report, researchers performing a phase-II study at seven medical centers in the United States, Germany, and Switzerland found that imetelstat produced rapid and durable hematologic and molecular responses in all 18 patients in their study of essential thrombocythemia refractory to other treatments. This result is particularly encouraging because current standard therapies “induce nonspecific reductions in platelet counts but do not typically eliminate or alter the biologic characteristics of the disease,” said Dr. Gabriela M. Baerlocher of the department of hematology and the Stem Cell Molecular Diagnostics Laboratory, University of Bern, Switzerland.

These study participants had either failed to respond to hydroxyurea, anagrelide, and interferon therapy or were forced to discontinue these agents because of adverse effects. After weekly treatment with imetelstat at one of two doses, 100% of the patients achieved a hematologic response, attaining platelet counts of 250,000-300,000 per cc. Sixteen participants (89%) achieved a complete hematologic response. The median time to complete response was 6.1 weeks, Dr. Baerlocher and her associates said (N Engl J Med. 2015 Sep 3. doi:10.1056/NEJMoa1503479).

After a median follow-up of 17 months on a maintenance dose of imetelstat, 10 patients were still receiving treatment. The median duration of response had not been reached as of press time (range, 5-30 months).

The most important adverse events were neutropenia (15 patients) and abnormal results on liver-function tests (14 patients). The treating physicians attributed 18 adverse events of grade 3 or higher to the study drug, including headache, anemia, and one syncopal episode. Other adverse events included fatigue, nausea, diarrhea, infections, and rash.

The telomerase inhibitor imetelstat showed promise against advanced myelofibrosis and essential thrombocythemia in two industry-funded preliminary studies, according to separate reports published online Sept. 3 in the New England Journal of Medicine.

In previous in vitro and animal studies, imetelstat inhibited the proliferation of various types of malignant cells but was not active in normal somatic tissue. Researchers assessed the agent for advanced myelofibrosis in part because, at present, only one available treatment – allogeneic stem-cell transplantation (ASCT) – sometimes induces long-term remission. ASCT carries a relatively high rate of treatment-related death and complications, and is contraindicated in many older patients.

In the first report, researchers conducted a small, single-center cohort study to collect preliminary data on the agent’s efficacy and safety in 33 patients with primary myelofibrosis (18 participants), myelofibrosis that was related to polycythemia (10 participants), or myelofibrosis associated with essential thrombocytopenia (10 participants). Imetelstat was administered in 2-hour intravenous infusions given in 3-week cycles, said Dr. Ayalew Tefferi of the division of hematology, Mayo Clinic, Rochester Minn.

©Ed Uthman/flickr.com

The median duration of treatment was 8.6 months (range, 1.4-21.7 months). Seven patients (21%) had either a complete or partial response; the 4 patients with a complete response had documented complete reversal of bone marrow fibrosis. The time to onset of response was 3.5 months (range, 1.4-7.2 months), and the median duration of response was 18 months (range, 13-20 months).

These remissions “confirm selective anticlonal activity, which has not previously been documented in drug treatment of myelofibrosis,” noted Dr. Tefferi and his associates (N Engl J Med 2015 Sep 3. doi:10.1056/NEJMoa1310523). Three of the seven patients who responded to imetelstat “had been heavily dependent on red-cell transfusions at study entry and became transfusion-independent and sustained a hemoglobin level of more than 10 g/dL for a minimum of 3 months during therapy,” they noted.

In addition, 8 of 10 patients who had marked leukocytosis at baseline had either a complete resolution (3 patients) or a reduction of at least 50% in white-cell counts (5 patients). All 11 participants who had thrombocytosis at baseline had either complete resolution (10 patients) or a reduction in platelet count of at least 50% (1 patient). Of the 27 participants who had leukoerythroblastosis at baseline, 22 showed either complete resolution (13 patients) or a reduction of at least 50% in the percentage of immature myeloid cells and nucleated red cells (9 patients). Also, 17 of the 21 participants who had at least 1% circulating blasts at baseline had either a complete disappearance of circulating blasts (14 patients) or a reduction of at least 50% (3 patients).

The most clinically significant adverse effect of imetelstat, myelosuppression, occurred in 22 patients (67%) and often necessitated dose reductions. Low-grade elevations in liver enzymes also were a concern. One patient died from an intracranial hemorrhage that the treating physician attributed to drug-induced grade 4 thrombocytopenia. Other adverse events that may or may not have been treatment related included fever, epistaxis, bruising, hematoma, lung infection, skin infection, and upper-GI hemorrhage.

These findings not only identify imetelstat as a possible treatment for myelofibrosis, they also suggest that other telomerase-targeting strategies may be beneficial in this disease, Dr. Tefferi and his associates added.

In the second report, researchers performing a phase-II study at seven medical centers in the United States, Germany, and Switzerland found that imetelstat produced rapid and durable hematologic and molecular responses in all 18 patients in their study of essential thrombocythemia refractory to other treatments. This result is particularly encouraging because current standard therapies “induce nonspecific reductions in platelet counts but do not typically eliminate or alter the biologic characteristics of the disease,” said Dr. Gabriela M. Baerlocher of the department of hematology and the Stem Cell Molecular Diagnostics Laboratory, University of Bern, Switzerland.

These study participants had either failed to respond to hydroxyurea, anagrelide, and interferon therapy or were forced to discontinue these agents because of adverse effects. After weekly treatment with imetelstat at one of two doses, 100% of the patients achieved a hematologic response, attaining platelet counts of 250,000-300,000 per cc. Sixteen participants (89%) achieved a complete hematologic response. The median time to complete response was 6.1 weeks, Dr. Baerlocher and her associates said (N Engl J Med. 2015 Sep 3. doi:10.1056/NEJMoa1503479).

After a median follow-up of 17 months on a maintenance dose of imetelstat, 10 patients were still receiving treatment. The median duration of response had not been reached as of press time (range, 5-30 months).

The most important adverse events were neutropenia (15 patients) and abnormal results on liver-function tests (14 patients). The treating physicians attributed 18 adverse events of grade 3 or higher to the study drug, including headache, anemia, and one syncopal episode. Other adverse events included fatigue, nausea, diarrhea, infections, and rash.

DNA methylation

Image by Christoph Bock

Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.

The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.

The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.

They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.

“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.

Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.

The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m² to 125 mg/m².

The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).

The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.

Safety and efficacy

The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).

The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).

There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m² daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m² daily × 5. The maximum tolerated dose was not reached in patients with AML.

Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m². So the team recommended this as the phase 2 dose.

A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.

Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.

DNA methylation

Image by Christoph Bock

Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.

The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.

The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.

They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.

“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.

Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.

The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m² to 125 mg/m².

The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).

The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.

Safety and efficacy

The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).

The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).

There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m² daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m² daily × 5. The maximum tolerated dose was not reached in patients with AML.

Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m². So the team recommended this as the phase 2 dose.

A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.

Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.

DNA methylation

Image by Christoph Bock

Investigators say a novel hypomethylating agent (HMA) is safe and clinically active in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) who have failed standard therapy.

The HMA, guadecitabine (SGI-110), reverses aberrant DNA methylation by inhibiting DNA methyltransferase enzymes.

The investigators tested guadecitabine in a phase 1 study of patients with relapsed or refractory AML or MDS.

They reported the results in The Lancet Oncology. The study was sponsored by Astex Pharmaceuticals, the company developing guadecitabine.

“In this study, we observed induced clinical responses in heavily pretreated patients, including prior treatment with current HMAs,” said study author Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Together with the results of a large phase 2 study to be published later, these data support further investigation, including the recently commenced global phase 3 study in treatment-naïve AML patients”.

Dr Kantarjian and his colleagues enrolled 93 patients in the phase 1 study, 74 with AML and 19 with MDS. The patients had received 1 to 9 prior treatment regimens, and most had received prior azacitidine or decitabine.

The trial had a 3+3 dose-escalation design. Patients received guadecitabine doses ranging from 3 mg/m² to 125 mg/m².

The patients were also randomized to receive guadecitabine either once-daily for 5 consecutive days (35 AML, 9 MDS) or once-weekly (28 AML, 6 MDS) for 3 weeks in a 28-day treatment cycle. A twice-weekly treatment schedule was added to the study after a protocol amendment (11 AML, 4 MDS).

The investigators said the 3 treatment groups were well balanced with regard to baseline characteristics. However, the initial median bone marrow blast percentage in the daily × 5 group was twice that of the once-weekly and twice-weekly groups—42%, 19%, and 20%, respectively.

Safety and efficacy

The investigators said the treatment was well-tolerated. The most common grade 3 or higher adverse events were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%).

The most common serious adverse events were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).

There were 2 dose-limiting toxicities in MDS patients at the 125 mg/m² daily × 5 dose. So the maximum tolerated dose for these patients was 90 mg/m² daily × 5. The maximum tolerated dose was not reached in patients with AML.

Six patients with AML and 6 with MDS had a clinical response to guadecitabine. The investigators said potent, dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m². So the team recommended this as the phase 2 dose.

A phase 2 study of guadecitabine is ongoing. The study enrolled more than 300 patients with treatment-naïve or relapsed/refractory AML or MDS.

Investigators recently began an 800-patient, phase 3 study (ASTRAL-1), in which guadecitabine is being compared with physician’s choice of decitabine, azacitidine, or low-dose cytarabine in treatment-naïve AML patients who are not candidates for intensive induction chemotherapy.

Blood smear showing MDS

Treatment with lenalidomide can have a significant effect on pulmonary sarcoidosis in myelodysplastic syndrome (MDS), according to a case study.

The case was a 71-year-old woman with newly diagnosed 5q-MDS and a long-standing history of refractory pulmonary sarcoidosis.

After 2 cycles of treatment with lenalidomide, the patient had substantial improvements in lung function, fatigue, daily activity, and quality of life.

This case is the first of its kind to show the potential effects of lenalidomide as a therapeutic option in patients with pulmonary sarcoidosis.

Ali Bazargan, MD, of St. Vincent’s Hospital in Melbourne, Victoria, Australia, and his colleagues described this case in CHEST.

The patient had a 12-year history of stage IV pulmonary sarcoidosis with no extrapulmonary organ involvement. She had never smoked but had a history of hypertension that was managed with perindopril.

The patient presented with refractory and worsening dyspnea, despite receiving long-term therapy with methotrexate and inhaled and systemic corticosteroids. Before she began receiving lenalidomide, the patient was taking 15 mg of prednisolone and 400 mg of inhaled budesonide daily.

Blood tests revealed the patient had macrocytic anemia (hemoglobin level, 81 g/L; mean corpuscular volume, 114 fL).

A subsequent bone marrow biopsy revealed hypocellular marrow with trilineage dysplasia consistent with 5q-MDS but no evidence of noncaseating granulomas. So the patient began receiving lenalidomide at 10 mg daily.

While the researchers were trying to establish her diagnosis of 5q-MDS, the patient became transfusion-dependent and experienced severe dyspnea, fatigue, and a considerable decline in quality of life.

A chest CT scan revealed irregular masses in her lung, with bibasal alveolar infiltrates that had developed within a 12-month period.

However, after 2 cycles of lenalidomide, the patient had significant improvements in dyspnea, fatigue, daily activity, and quality of life. Lung function testing showed an increase in vital capacity from 1.73 L to 1.93 L.

And a chest CT scan performed 4 months after the patient began taking lenalidomide showed that the bibasal alveolar infiltrates had completely cleared.

During this period, the patient’s dose of prednisolone was reduced from 15 mg daily to 5 mg on alternate days, but she continues to receive the same dose of lenalidomide.

Blood smear showing MDS

Treatment with lenalidomide can have a significant effect on pulmonary sarcoidosis in myelodysplastic syndrome (MDS), according to a case study.

The case was a 71-year-old woman with newly diagnosed 5q-MDS and a long-standing history of refractory pulmonary sarcoidosis.

After 2 cycles of treatment with lenalidomide, the patient had substantial improvements in lung function, fatigue, daily activity, and quality of life.

This case is the first of its kind to show the potential effects of lenalidomide as a therapeutic option in patients with pulmonary sarcoidosis.

Ali Bazargan, MD, of St. Vincent’s Hospital in Melbourne, Victoria, Australia, and his colleagues described this case in CHEST.

The patient had a 12-year history of stage IV pulmonary sarcoidosis with no extrapulmonary organ involvement. She had never smoked but had a history of hypertension that was managed with perindopril.

The patient presented with refractory and worsening dyspnea, despite receiving long-term therapy with methotrexate and inhaled and systemic corticosteroids. Before she began receiving lenalidomide, the patient was taking 15 mg of prednisolone and 400 mg of inhaled budesonide daily.

Blood tests revealed the patient had macrocytic anemia (hemoglobin level, 81 g/L; mean corpuscular volume, 114 fL).

A subsequent bone marrow biopsy revealed hypocellular marrow with trilineage dysplasia consistent with 5q-MDS but no evidence of noncaseating granulomas. So the patient began receiving lenalidomide at 10 mg daily.

While the researchers were trying to establish her diagnosis of 5q-MDS, the patient became transfusion-dependent and experienced severe dyspnea, fatigue, and a considerable decline in quality of life.

A chest CT scan revealed irregular masses in her lung, with bibasal alveolar infiltrates that had developed within a 12-month period.

However, after 2 cycles of lenalidomide, the patient had significant improvements in dyspnea, fatigue, daily activity, and quality of life. Lung function testing showed an increase in vital capacity from 1.73 L to 1.93 L.

And a chest CT scan performed 4 months after the patient began taking lenalidomide showed that the bibasal alveolar infiltrates had completely cleared.

During this period, the patient’s dose of prednisolone was reduced from 15 mg daily to 5 mg on alternate days, but she continues to receive the same dose of lenalidomide.

Blood smear showing MDS

Treatment with lenalidomide can have a significant effect on pulmonary sarcoidosis in myelodysplastic syndrome (MDS), according to a case study.

The case was a 71-year-old woman with newly diagnosed 5q-MDS and a long-standing history of refractory pulmonary sarcoidosis.

After 2 cycles of treatment with lenalidomide, the patient had substantial improvements in lung function, fatigue, daily activity, and quality of life.

This case is the first of its kind to show the potential effects of lenalidomide as a therapeutic option in patients with pulmonary sarcoidosis.

Ali Bazargan, MD, of St. Vincent’s Hospital in Melbourne, Victoria, Australia, and his colleagues described this case in CHEST.

The patient had a 12-year history of stage IV pulmonary sarcoidosis with no extrapulmonary organ involvement. She had never smoked but had a history of hypertension that was managed with perindopril.

The patient presented with refractory and worsening dyspnea, despite receiving long-term therapy with methotrexate and inhaled and systemic corticosteroids. Before she began receiving lenalidomide, the patient was taking 15 mg of prednisolone and 400 mg of inhaled budesonide daily.

Blood tests revealed the patient had macrocytic anemia (hemoglobin level, 81 g/L; mean corpuscular volume, 114 fL).

A subsequent bone marrow biopsy revealed hypocellular marrow with trilineage dysplasia consistent with 5q-MDS but no evidence of noncaseating granulomas. So the patient began receiving lenalidomide at 10 mg daily.

While the researchers were trying to establish her diagnosis of 5q-MDS, the patient became transfusion-dependent and experienced severe dyspnea, fatigue, and a considerable decline in quality of life.

A chest CT scan revealed irregular masses in her lung, with bibasal alveolar infiltrates that had developed within a 12-month period.

However, after 2 cycles of lenalidomide, the patient had significant improvements in dyspnea, fatigue, daily activity, and quality of life. Lung function testing showed an increase in vital capacity from 1.73 L to 1.93 L.

And a chest CT scan performed 4 months after the patient began taking lenalidomide showed that the bibasal alveolar infiltrates had completely cleared.

During this period, the patient’s dose of prednisolone was reduced from 15 mg daily to 5 mg on alternate days, but she continues to receive the same dose of lenalidomide.

Red and white blood cells

A small molecule that targets the sonic Hedgehog signaling pathway has advanced to phase 2 trials in a range of hematologic disorders.

In a phase 1 study, the inhibitor, PF-04449913, exhibited activity in adults with leukemias, myelodysplastic syndromes (MDS), and myelofibrosis (MF).

Sixty percent of the patients studied experienced treatment-related adverse events (AEs), but there were no treatment-related deaths. Most deaths were disease-related.

Researchers detailed the results of this trial in The Lancet Haematology. The study was funded by Pfizer, the company developing PF-04449913, as well as the California Institute for Regenerative Medicine and European Leukemia Net.

Preclinical research showed that PF-04449913 forces dormant cancer stem cells in the bone marrow to begin differentiating and exit into the blood stream where they can be destroyed by chemotherapy agents targeting dividing cells.

“This drug gets that unwanted house guests to leave and never come back,” said Catriona Jamieson, MD, PhD, of University of California, San Diego School of Medicine.

“It’s a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome, and myelofibrosis. It’s a bonus that the drug can be administered as easily as an aspirin, in a single, daily, oral tablet.”

For the first-in-human study, Dr Jamieson and her colleagues evaluated PF-04449913 in 47 adult patients. Twenty-eight of them had acute myeloid leukemia (AML), 6 had MDS, 5 had chronic myeloid leukemia (CML), 1 had chronic myelomonocytic leukemia (CMML), and 7 had MF.

Eighty-five percent of patients (n=40) had an ECOG performance status of 0-1. Eighty-one percent (n=38) had received previous systemic treatment, and 47% (n=22) had received 3 or more previous treatment regimens.

Patients received escalating daily doses of PF-04449913 in 28-day cycles. Treatment cycles were repeated until a patient experienced unacceptable AEs without evidence of clinical improvement. Patients who showed clinical activity without experiencing serious AEs received additional treatment cycles.

Dosing and AEs

Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), or 600 mg (n=5).

The researchers found the maximum-tolerated dose to be 400 mg once daily. The mean half-life was 23.9 hours in this dose group, and pharmacokinetics seemed to be dose-proportional.

Two patients experienced dose-limiting toxicities, 1 in the 80 mg group (grade 3 hypoxia and grade 3 pleural effusion), and 1 in the 600 mg group (grade 3 peripheral edema).

In all, 60% of patients (n=28) experienced treatment-related AEs. The most common were dysgeusia (28%), decreased appetite (19%), and alopecia (15%). There were 3 grade 4 AEs—1 case of neutropenia and 2 cases of thrombocytopenia.

There were 15 deaths, none of which were treatment-related. Eleven deaths were disease-related, and the remaining 4 were related to infection.

Clinical activity

The researchers said there was “some suggestion of clinical activity” in 23 patients (49%).

Of the 5 patients with CML (2 chronic phase and 3 blast phase), 1 patient with blast phase CML had a partial cytogenetic response to PF-04449913.

Of the 6 patients with MDS and 1 with CMML, 4 had stable disease after treatment. Two of these patients had hematologic improvement.

Two of the 7 patients with MF had clinical improvement.

Of the 28 patients with AML, 16 showed evidence of possible biological activity. One patient had a complete response and 4 had a partial response with incomplete hematologic recovery. Four AML patients had minor responses, and 7 had stable disease.

Given these results, PF-04449913 is now being investigated in 5 phase 2 trials of hematologic disorders, 4 of which are recruiting participants.

“Our hope is that this drug will enable more effective treatment to begin earlier and that, with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation,” Dr Jamieson said. “It’s all about reducing the burden of disease by intervening early.”

Red and white blood cells

A small molecule that targets the sonic Hedgehog signaling pathway has advanced to phase 2 trials in a range of hematologic disorders.

In a phase 1 study, the inhibitor, PF-04449913, exhibited activity in adults with leukemias, myelodysplastic syndromes (MDS), and myelofibrosis (MF).

Sixty percent of the patients studied experienced treatment-related adverse events (AEs), but there were no treatment-related deaths. Most deaths were disease-related.

Researchers detailed the results of this trial in The Lancet Haematology. The study was funded by Pfizer, the company developing PF-04449913, as well as the California Institute for Regenerative Medicine and European Leukemia Net.

Preclinical research showed that PF-04449913 forces dormant cancer stem cells in the bone marrow to begin differentiating and exit into the blood stream where they can be destroyed by chemotherapy agents targeting dividing cells.

“This drug gets that unwanted house guests to leave and never come back,” said Catriona Jamieson, MD, PhD, of University of California, San Diego School of Medicine.

“It’s a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome, and myelofibrosis. It’s a bonus that the drug can be administered as easily as an aspirin, in a single, daily, oral tablet.”

For the first-in-human study, Dr Jamieson and her colleagues evaluated PF-04449913 in 47 adult patients. Twenty-eight of them had acute myeloid leukemia (AML), 6 had MDS, 5 had chronic myeloid leukemia (CML), 1 had chronic myelomonocytic leukemia (CMML), and 7 had MF.

Eighty-five percent of patients (n=40) had an ECOG performance status of 0-1. Eighty-one percent (n=38) had received previous systemic treatment, and 47% (n=22) had received 3 or more previous treatment regimens.

Patients received escalating daily doses of PF-04449913 in 28-day cycles. Treatment cycles were repeated until a patient experienced unacceptable AEs without evidence of clinical improvement. Patients who showed clinical activity without experiencing serious AEs received additional treatment cycles.

Dosing and AEs

Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), or 600 mg (n=5).

The researchers found the maximum-tolerated dose to be 400 mg once daily. The mean half-life was 23.9 hours in this dose group, and pharmacokinetics seemed to be dose-proportional.

Two patients experienced dose-limiting toxicities, 1 in the 80 mg group (grade 3 hypoxia and grade 3 pleural effusion), and 1 in the 600 mg group (grade 3 peripheral edema).

In all, 60% of patients (n=28) experienced treatment-related AEs. The most common were dysgeusia (28%), decreased appetite (19%), and alopecia (15%). There were 3 grade 4 AEs—1 case of neutropenia and 2 cases of thrombocytopenia.

There were 15 deaths, none of which were treatment-related. Eleven deaths were disease-related, and the remaining 4 were related to infection.

Clinical activity

The researchers said there was “some suggestion of clinical activity” in 23 patients (49%).

Of the 5 patients with CML (2 chronic phase and 3 blast phase), 1 patient with blast phase CML had a partial cytogenetic response to PF-04449913.

Of the 6 patients with MDS and 1 with CMML, 4 had stable disease after treatment. Two of these patients had hematologic improvement.

Two of the 7 patients with MF had clinical improvement.

Of the 28 patients with AML, 16 showed evidence of possible biological activity. One patient had a complete response and 4 had a partial response with incomplete hematologic recovery. Four AML patients had minor responses, and 7 had stable disease.

Given these results, PF-04449913 is now being investigated in 5 phase 2 trials of hematologic disorders, 4 of which are recruiting participants.

“Our hope is that this drug will enable more effective treatment to begin earlier and that, with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation,” Dr Jamieson said. “It’s all about reducing the burden of disease by intervening early.”

Red and white blood cells

A small molecule that targets the sonic Hedgehog signaling pathway has advanced to phase 2 trials in a range of hematologic disorders.

In a phase 1 study, the inhibitor, PF-04449913, exhibited activity in adults with leukemias, myelodysplastic syndromes (MDS), and myelofibrosis (MF).

Sixty percent of the patients studied experienced treatment-related adverse events (AEs), but there were no treatment-related deaths. Most deaths were disease-related.

Researchers detailed the results of this trial in The Lancet Haematology. The study was funded by Pfizer, the company developing PF-04449913, as well as the California Institute for Regenerative Medicine and European Leukemia Net.

Preclinical research showed that PF-04449913 forces dormant cancer stem cells in the bone marrow to begin differentiating and exit into the blood stream where they can be destroyed by chemotherapy agents targeting dividing cells.

“This drug gets that unwanted house guests to leave and never come back,” said Catriona Jamieson, MD, PhD, of University of California, San Diego School of Medicine.

“It’s a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome, and myelofibrosis. It’s a bonus that the drug can be administered as easily as an aspirin, in a single, daily, oral tablet.”

For the first-in-human study, Dr Jamieson and her colleagues evaluated PF-04449913 in 47 adult patients. Twenty-eight of them had acute myeloid leukemia (AML), 6 had MDS, 5 had chronic myeloid leukemia (CML), 1 had chronic myelomonocytic leukemia (CMML), and 7 had MF.

Eighty-five percent of patients (n=40) had an ECOG performance status of 0-1. Eighty-one percent (n=38) had received previous systemic treatment, and 47% (n=22) had received 3 or more previous treatment regimens.

Patients received escalating daily doses of PF-04449913 in 28-day cycles. Treatment cycles were repeated until a patient experienced unacceptable AEs without evidence of clinical improvement. Patients who showed clinical activity without experiencing serious AEs received additional treatment cycles.

Dosing and AEs

Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), or 600 mg (n=5).

The researchers found the maximum-tolerated dose to be 400 mg once daily. The mean half-life was 23.9 hours in this dose group, and pharmacokinetics seemed to be dose-proportional.

Two patients experienced dose-limiting toxicities, 1 in the 80 mg group (grade 3 hypoxia and grade 3 pleural effusion), and 1 in the 600 mg group (grade 3 peripheral edema).

In all, 60% of patients (n=28) experienced treatment-related AEs. The most common were dysgeusia (28%), decreased appetite (19%), and alopecia (15%). There were 3 grade 4 AEs—1 case of neutropenia and 2 cases of thrombocytopenia.

There were 15 deaths, none of which were treatment-related. Eleven deaths were disease-related, and the remaining 4 were related to infection.

Clinical activity

The researchers said there was “some suggestion of clinical activity” in 23 patients (49%).

Of the 5 patients with CML (2 chronic phase and 3 blast phase), 1 patient with blast phase CML had a partial cytogenetic response to PF-04449913.

Of the 6 patients with MDS and 1 with CMML, 4 had stable disease after treatment. Two of these patients had hematologic improvement.

Two of the 7 patients with MF had clinical improvement.

Of the 28 patients with AML, 16 showed evidence of possible biological activity. One patient had a complete response and 4 had a partial response with incomplete hematologic recovery. Four AML patients had minor responses, and 7 had stable disease.

Given these results, PF-04449913 is now being investigated in 5 phase 2 trials of hematologic disorders, 4 of which are recruiting participants.

“Our hope is that this drug will enable more effective treatment to begin earlier and that, with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation,” Dr Jamieson said. “It’s all about reducing the burden of disease by intervening early.”

Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.

The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.

“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.

Wikimedia Commons, Uploaded by Paulo Mourao

Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).

In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).

Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.

When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.

Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.

Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.

The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.

“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.

Wikimedia Commons, Uploaded by Paulo Mourao

Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).

In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).

Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.

When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.

Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.

Among patients with refractory anemia with ring sideroblasts, the presence of a common mutation in SF3B1 appears to be a marker for an indolent clinical course and favorable outcome compared to patients with wild-type SF3B1, European investigators reported.

The gene SF3B1, which encodes for a splicing factor subunit, is frequently mutated in cases of chronic lymphocytic leukemia and myelodysplastic syndromes.

“SF3B1 mutation is a major determinant of disease phenotype and clinical outcome in MDS [myelodysplastic syndrome] with ring sideroblasts. SF3B1-mutated MDS is characterized by homogeneous hematologic features, favorable prognosis, and restricted patterns of co-mutated genes and clonal evolution. Overall, these results strongly support the recognition of MDS associated with SF3B1 mutation as a distinct MDS subtype. Conversely, SF3B1-negative MDS with ring sideroblasts represents a subset with a high prevalence of TP53 mutations and worse outcome that should be taken into consideration in clinical decision-making,” the study authors conclude.

Wikimedia Commons, Uploaded by Paulo Mourao

Dr. Luca Malcovati and his colleagues from the University of Pavia, Italy, and other European centers, conducted a mutational analysis of 293 patients with myeloid neoplasms and 1% or more ring sideroblasts. They found somatic mutations in SF3B1 in 129 of 159 patients with refractory anemia with ring sideroblasts (RARS) or refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). In contrast, there was a significantly lower prevalence of SF3B1 mutations among 50 patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and among 84 additional patients with other myeloid diseases under the World Health Organization classification of disorders of hematopoietic and lymphoid tissues (P < .001).

In multivariable analyses controlling for demographic and disease-related factors, patients with SF3B1 mutations had significantly better overall survival (hazard ratio, 0.37; P = .003), as well as a lower cumulative incidence of disease progression (HR, 0.31; P = .018), compared with patients with wild-type SF3B1 (Blood 2015;126[2]:233-41).

Mutations in SF3B1 were predictive of better outcomes among patients with RARS, RCMD-RS, and in patients with MDS without excess blasts.

When they looked at other mutations, the investigators found that in patients with SF3B1 mutations, the mutations in DNA methylation genes were associated with the presence of multilineage dysplasia, but this association had no significant effect on clinical outcomes.

Among patients with wild-type SB3B1, mutations in TP53 were frequently seen, and these mutations were associated with poor outcomes.

Clonal hematopoiesis was detected in DNA samples from approximately half of 439 patients with aplastic anemia, and a third of the study population carried mutations in candidate genes that correlated with clinical outcomes, according to a report published online July 2 in the New England Journal of Medicine.

Most patients with aplastic anemia respond to immunosuppressive therapy or bone marrow transplantation, but about 15% later develop myelodysplastic syndromes, acute myeloid leukemia (AML), or both. Historically, this has been attributed to “clonal evolution,” but a more accurate term is clonal hematopoiesis. However, not all patients with clonal hematopoiesis go on to develop late myelodysplastic syndromes or AML, said Dr. Tetsuichi Yoshizato of the department of pathology and tumor biology at Kyoto (Japan) University and associates.

To clarify the role of clonal hematopoiesis in aplastic anemia, the investigators analyzed DNA in blood, bone marrow, and buccal samples from 439 patients with bone marrow failure who were treated at three specialized centers in the United States and Japan.

Targeted sequencing of a panel of genes that are recurrently mutated in myeloid cancers was performed; 249 mutations were detected in candidate genes for myelodysplastic syndromes/AML in 36% of the study population. And about one-third of patients whose DNA harbored mutations had multiple (as many as 7) mutations. The most frequently mutated genes were BCOR and BCORL1 (in 9.3% of patients), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%), which together accounted for 77% of all mutation-positive patients, the investigators reported.

In addition, 47% of patients had expanded hematopoietic cell clones. Clones carrying certain mutations were associated with a better response to immunosuppressive treatment, while clones carrying several other mutations were associated with a poor treatment response, lower survival, and progression to myelodysplastic syndromes/AML. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and better overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes.

The pattern of mutations in individual patients, however, varied markedly over time and was often unpredictable. “It should be underscored that the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative,” Dr. Yoshizato and associates said (N. Engl. J. Med. 2015 July 2 [doi:10.1056/NEJMoa1414799]).

Although further genetic research is needed before these findings can be applied clinically to guide prognosis and treatment, they already “have implications for bone marrow failure, for early events in leukemogenesis, and for normal aging,” the investigators added.

Clonal hematopoiesis was detected in DNA samples from approximately half of 439 patients with aplastic anemia, and a third of the study population carried mutations in candidate genes that correlated with clinical outcomes, according to a report published online July 2 in the New England Journal of Medicine.

Most patients with aplastic anemia respond to immunosuppressive therapy or bone marrow transplantation, but about 15% later develop myelodysplastic syndromes, acute myeloid leukemia (AML), or both. Historically, this has been attributed to “clonal evolution,” but a more accurate term is clonal hematopoiesis. However, not all patients with clonal hematopoiesis go on to develop late myelodysplastic syndromes or AML, said Dr. Tetsuichi Yoshizato of the department of pathology and tumor biology at Kyoto (Japan) University and associates.

To clarify the role of clonal hematopoiesis in aplastic anemia, the investigators analyzed DNA in blood, bone marrow, and buccal samples from 439 patients with bone marrow failure who were treated at three specialized centers in the United States and Japan.

Targeted sequencing of a panel of genes that are recurrently mutated in myeloid cancers was performed; 249 mutations were detected in candidate genes for myelodysplastic syndromes/AML in 36% of the study population. And about one-third of patients whose DNA harbored mutations had multiple (as many as 7) mutations. The most frequently mutated genes were BCOR and BCORL1 (in 9.3% of patients), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%), which together accounted for 77% of all mutation-positive patients, the investigators reported.

In addition, 47% of patients had expanded hematopoietic cell clones. Clones carrying certain mutations were associated with a better response to immunosuppressive treatment, while clones carrying several other mutations were associated with a poor treatment response, lower survival, and progression to myelodysplastic syndromes/AML. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and better overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes.

The pattern of mutations in individual patients, however, varied markedly over time and was often unpredictable. “It should be underscored that the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative,” Dr. Yoshizato and associates said (N. Engl. J. Med. 2015 July 2 [doi:10.1056/NEJMoa1414799]).

Although further genetic research is needed before these findings can be applied clinically to guide prognosis and treatment, they already “have implications for bone marrow failure, for early events in leukemogenesis, and for normal aging,” the investigators added.

Clonal hematopoiesis was detected in DNA samples from approximately half of 439 patients with aplastic anemia, and a third of the study population carried mutations in candidate genes that correlated with clinical outcomes, according to a report published online July 2 in the New England Journal of Medicine.

Most patients with aplastic anemia respond to immunosuppressive therapy or bone marrow transplantation, but about 15% later develop myelodysplastic syndromes, acute myeloid leukemia (AML), or both. Historically, this has been attributed to “clonal evolution,” but a more accurate term is clonal hematopoiesis. However, not all patients with clonal hematopoiesis go on to develop late myelodysplastic syndromes or AML, said Dr. Tetsuichi Yoshizato of the department of pathology and tumor biology at Kyoto (Japan) University and associates.

To clarify the role of clonal hematopoiesis in aplastic anemia, the investigators analyzed DNA in blood, bone marrow, and buccal samples from 439 patients with bone marrow failure who were treated at three specialized centers in the United States and Japan.

Targeted sequencing of a panel of genes that are recurrently mutated in myeloid cancers was performed; 249 mutations were detected in candidate genes for myelodysplastic syndromes/AML in 36% of the study population. And about one-third of patients whose DNA harbored mutations had multiple (as many as 7) mutations. The most frequently mutated genes were BCOR and BCORL1 (in 9.3% of patients), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%), which together accounted for 77% of all mutation-positive patients, the investigators reported.

In addition, 47% of patients had expanded hematopoietic cell clones. Clones carrying certain mutations were associated with a better response to immunosuppressive treatment, while clones carrying several other mutations were associated with a poor treatment response, lower survival, and progression to myelodysplastic syndromes/AML. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and better overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes.

The pattern of mutations in individual patients, however, varied markedly over time and was often unpredictable. “It should be underscored that the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative,” Dr. Yoshizato and associates said (N. Engl. J. Med. 2015 July 2 [doi:10.1056/NEJMoa1414799]).

Although further genetic research is needed before these findings can be applied clinically to guide prognosis and treatment, they already “have implications for bone marrow failure, for early events in leukemogenesis, and for normal aging,” the investigators added.