Non-Hodgkin Lymphoma

Withania somnifera

The active compound in a plant extract has shown promise for treating non-Hodgkin lymphomas (NHLs), according to researchers.

The compound, withaferin A, is a steroidal lactone isolated from the Ayruvedic medicinal plant Ashwagandha (Withania somnifera).

Withaferin A has previously exhibited activity against a range of solid tumor malignancies, but its effects in NHLs and other hematologic malignancies have not been well-studied.

So Subbarao Bondada, PhD, of the University of Kentucky in Lexington, and his colleagues tested withaferin A in NHLs and reported their results in Cancer Biology and Therapy.

Withaferin A exhibited activity in several human B-cell lymphoma cell lines—the diffuse large B-cell lymphoma (DLBCL) cell lines LY-3, LY-10, and SudHL-6; the Burkitt lymphoma cell lines Raji and Ramos; and the mantle cell lymphoma cell line MINO.

Ramos was the most sensitive to withaferin A, and the mantle cell lymphoma cell line JEKO was the most resistant. The researchers said they are still investigating this resistance.

Withaferin A also inhibited the growth of the murine immature B-cell lymphoma cell line BKS-2 and the germinal center lymphoma cell line A20-Luc/YFP.

Further investigation revealed that withaferin A induces cell-cycle arrest, prompts apoptosis, inhibits NF-kB nuclear translocation, and reduces the expression of pro-survival signals in B-cell lymphomas.

The researchers also found evidence to suggest that withaferin A inhibits the activity of Hsp90. Although Hsp90 levels were unaltered in withaferin-A-treated lymphoma cells, the team observed a “robust” increase in Hsp70 expression levels (which suggests a decrease in Hsp90 function).

Finally, the researchers tested withaferin A in mice injected with the murine DLBCL line A20-Luc. The treatment proved active against A20-Luc cells but did not affect other proliferating cells.

Mice treated with withaferin A had a significant reduction in tumor size, compared to placebo-treated mice, on days 10 and 13 (P<0.05).

Based on these results, the researchers concluded that withaferin A may hold promise for treating NHL, particularly DLBCL.

“It may be possible to develop orally administered versions of withaferin A that could be used in lymphoma patients with fewer side effects than current chemotherapy regimens,” Dr Bondada said.

He and his colleagues are now testing withaferin A in chronic lymphocytic leukemia.

Withania somnifera

The active compound in a plant extract has shown promise for treating non-Hodgkin lymphomas (NHLs), according to researchers.

The compound, withaferin A, is a steroidal lactone isolated from the Ayruvedic medicinal plant Ashwagandha (Withania somnifera).

Withaferin A has previously exhibited activity against a range of solid tumor malignancies, but its effects in NHLs and other hematologic malignancies have not been well-studied.

So Subbarao Bondada, PhD, of the University of Kentucky in Lexington, and his colleagues tested withaferin A in NHLs and reported their results in Cancer Biology and Therapy.

Withaferin A exhibited activity in several human B-cell lymphoma cell lines—the diffuse large B-cell lymphoma (DLBCL) cell lines LY-3, LY-10, and SudHL-6; the Burkitt lymphoma cell lines Raji and Ramos; and the mantle cell lymphoma cell line MINO.

Ramos was the most sensitive to withaferin A, and the mantle cell lymphoma cell line JEKO was the most resistant. The researchers said they are still investigating this resistance.

Withaferin A also inhibited the growth of the murine immature B-cell lymphoma cell line BKS-2 and the germinal center lymphoma cell line A20-Luc/YFP.

Further investigation revealed that withaferin A induces cell-cycle arrest, prompts apoptosis, inhibits NF-kB nuclear translocation, and reduces the expression of pro-survival signals in B-cell lymphomas.

The researchers also found evidence to suggest that withaferin A inhibits the activity of Hsp90. Although Hsp90 levels were unaltered in withaferin-A-treated lymphoma cells, the team observed a “robust” increase in Hsp70 expression levels (which suggests a decrease in Hsp90 function).

Finally, the researchers tested withaferin A in mice injected with the murine DLBCL line A20-Luc. The treatment proved active against A20-Luc cells but did not affect other proliferating cells.

Mice treated with withaferin A had a significant reduction in tumor size, compared to placebo-treated mice, on days 10 and 13 (P<0.05).

Based on these results, the researchers concluded that withaferin A may hold promise for treating NHL, particularly DLBCL.

“It may be possible to develop orally administered versions of withaferin A that could be used in lymphoma patients with fewer side effects than current chemotherapy regimens,” Dr Bondada said.

He and his colleagues are now testing withaferin A in chronic lymphocytic leukemia.

Withania somnifera

The active compound in a plant extract has shown promise for treating non-Hodgkin lymphomas (NHLs), according to researchers.

The compound, withaferin A, is a steroidal lactone isolated from the Ayruvedic medicinal plant Ashwagandha (Withania somnifera).

Withaferin A has previously exhibited activity against a range of solid tumor malignancies, but its effects in NHLs and other hematologic malignancies have not been well-studied.

So Subbarao Bondada, PhD, of the University of Kentucky in Lexington, and his colleagues tested withaferin A in NHLs and reported their results in Cancer Biology and Therapy.

Withaferin A exhibited activity in several human B-cell lymphoma cell lines—the diffuse large B-cell lymphoma (DLBCL) cell lines LY-3, LY-10, and SudHL-6; the Burkitt lymphoma cell lines Raji and Ramos; and the mantle cell lymphoma cell line MINO.

Ramos was the most sensitive to withaferin A, and the mantle cell lymphoma cell line JEKO was the most resistant. The researchers said they are still investigating this resistance.

Withaferin A also inhibited the growth of the murine immature B-cell lymphoma cell line BKS-2 and the germinal center lymphoma cell line A20-Luc/YFP.

Further investigation revealed that withaferin A induces cell-cycle arrest, prompts apoptosis, inhibits NF-kB nuclear translocation, and reduces the expression of pro-survival signals in B-cell lymphomas.

The researchers also found evidence to suggest that withaferin A inhibits the activity of Hsp90. Although Hsp90 levels were unaltered in withaferin-A-treated lymphoma cells, the team observed a “robust” increase in Hsp70 expression levels (which suggests a decrease in Hsp90 function).

Finally, the researchers tested withaferin A in mice injected with the murine DLBCL line A20-Luc. The treatment proved active against A20-Luc cells but did not affect other proliferating cells.

Mice treated with withaferin A had a significant reduction in tumor size, compared to placebo-treated mice, on days 10 and 13 (P<0.05).

Based on these results, the researchers concluded that withaferin A may hold promise for treating NHL, particularly DLBCL.

“It may be possible to develop orally administered versions of withaferin A that could be used in lymphoma patients with fewer side effects than current chemotherapy regimens,” Dr Bondada said.

He and his colleagues are now testing withaferin A in chronic lymphocytic leukemia.

Mantle cell lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has adopted a positive opinion recommending that KTE-C19 receive orphan designation to treat primary mediastinal B-cell lymphoma (PMBCL) and mantle cell lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

No other product candidate currently has orphan drug designation for the treatment of PMBCL in the European Union (EU).

KTE-C19 already has orphan drug designation to treat diffuse large B-cell lymphoma (DLBCL) in the US and the EU.

“We are conducting a phase 1/2 clinical trial of KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma, including DLBCL and PMBCL, and plan to report initial topline results from the phase 1 portion of the trial later this year [at the ASH Annual Meeting],” said Arie Belldegrun, MD, Chairman, President, and Chief Executive Officer of Kite Pharmaceuticals, the company developing KTE-C19.

Trial results

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

About orphan designation

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Mantle cell lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has adopted a positive opinion recommending that KTE-C19 receive orphan designation to treat primary mediastinal B-cell lymphoma (PMBCL) and mantle cell lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

No other product candidate currently has orphan drug designation for the treatment of PMBCL in the European Union (EU).

KTE-C19 already has orphan drug designation to treat diffuse large B-cell lymphoma (DLBCL) in the US and the EU.

“We are conducting a phase 1/2 clinical trial of KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma, including DLBCL and PMBCL, and plan to report initial topline results from the phase 1 portion of the trial later this year [at the ASH Annual Meeting],” said Arie Belldegrun, MD, Chairman, President, and Chief Executive Officer of Kite Pharmaceuticals, the company developing KTE-C19.

Trial results

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

About orphan designation

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Mantle cell lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has adopted a positive opinion recommending that KTE-C19 receive orphan designation to treat primary mediastinal B-cell lymphoma (PMBCL) and mantle cell lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

No other product candidate currently has orphan drug designation for the treatment of PMBCL in the European Union (EU).

KTE-C19 already has orphan drug designation to treat diffuse large B-cell lymphoma (DLBCL) in the US and the EU.

“We are conducting a phase 1/2 clinical trial of KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma, including DLBCL and PMBCL, and plan to report initial topline results from the phase 1 portion of the trial later this year [at the ASH Annual Meeting],” said Arie Belldegrun, MD, Chairman, President, and Chief Executive Officer of Kite Pharmaceuticals, the company developing KTE-C19.

Trial results

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

About orphan designation

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

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.

Patient receiving chemotherapy

Photo by Rhoda Baer

Last March, the US Food and Drug Administration (FDA) issued a statement warning healthcare professionals not to use the chemotherapy drug Treanda Injection (bendamustine hydrochloride) with closed system transfer devices (CSTDs), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).

Now, the FDA is providing a list of devices that were tested and deemed compatible with the drug (see the tables below).

The devices were tested by Treanda’s manufacturer, Teva Pharmaceuticals.

Treanda is used to treat patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Treanda is available in 2 formulations: a solution, Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution), and a lyophilized powder, Treanda for Injection (25 mg/vial or 100 mg/vial lyophilized powder).  The information discussed here is referring to compatibility with the solution, Treanda Injection.

Treanda Injection contains N, N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA in the drug.

This incompatibility leads to device failure, such as leaking, breaking, or operational failure of CSTD components; possible product contamination; and potential serious adverse health consequences to practitioners, such as skin reactions, or to patients, including the risk of small blood vessel blockage if the product is contaminated with dissolved ABS or polycarbonate.

Users should contact device manufacturers prior to using the specific devices listed below to ensure there have been no changes made to the material composition of the devices and that the devices are compatible with Treanda use.

Table 1. The compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, and gloves (based on testing conducted by Teva from February 2015 through June 2015).

*Part numbers reflect a specific size glove used in the compatibility tests.

Table 2. The IV administration set found to be compatible with Treanda Injection after dilution in a 500 mL 0.9% sodium chloride IV infusion bags (based on testing conducted by Teva from February 2015 through June 2015*).

*Compatibility studies did not include testing with 2.5% dextrose/0.45% sodium chloride injection. However, the results of these studies are not expected to change. So either diluent, 0.9% sodium chloride or 2.5% dextrose/0.45% sodium chloride injection, can be used with Treanda injection.

The FDA required label changes for both the solution and the powder formulations of Treanda to include information for safe preparation and handling for IV administration. See the full prescribing information for details.

For more details on the compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, gloves, and IV administration sets, see Teva’s Dear Health Care Provider letter.

Adverse events or quality problems associated with the use of Treanda products can be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Patient receiving chemotherapy

Photo by Rhoda Baer

Last March, the US Food and Drug Administration (FDA) issued a statement warning healthcare professionals not to use the chemotherapy drug Treanda Injection (bendamustine hydrochloride) with closed system transfer devices (CSTDs), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).

Now, the FDA is providing a list of devices that were tested and deemed compatible with the drug (see the tables below).

The devices were tested by Treanda’s manufacturer, Teva Pharmaceuticals.

Treanda is used to treat patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Treanda is available in 2 formulations: a solution, Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution), and a lyophilized powder, Treanda for Injection (25 mg/vial or 100 mg/vial lyophilized powder).  The information discussed here is referring to compatibility with the solution, Treanda Injection.

Treanda Injection contains N, N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA in the drug.

This incompatibility leads to device failure, such as leaking, breaking, or operational failure of CSTD components; possible product contamination; and potential serious adverse health consequences to practitioners, such as skin reactions, or to patients, including the risk of small blood vessel blockage if the product is contaminated with dissolved ABS or polycarbonate.

Users should contact device manufacturers prior to using the specific devices listed below to ensure there have been no changes made to the material composition of the devices and that the devices are compatible with Treanda use.

Table 1. The compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, and gloves (based on testing conducted by Teva from February 2015 through June 2015).

*Part numbers reflect a specific size glove used in the compatibility tests.

Table 2. The IV administration set found to be compatible with Treanda Injection after dilution in a 500 mL 0.9% sodium chloride IV infusion bags (based on testing conducted by Teva from February 2015 through June 2015*).

*Compatibility studies did not include testing with 2.5% dextrose/0.45% sodium chloride injection. However, the results of these studies are not expected to change. So either diluent, 0.9% sodium chloride or 2.5% dextrose/0.45% sodium chloride injection, can be used with Treanda injection.

The FDA required label changes for both the solution and the powder formulations of Treanda to include information for safe preparation and handling for IV administration. See the full prescribing information for details.

For more details on the compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, gloves, and IV administration sets, see Teva’s Dear Health Care Provider letter.

Adverse events or quality problems associated with the use of Treanda products can be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Patient receiving chemotherapy

Photo by Rhoda Baer

Last March, the US Food and Drug Administration (FDA) issued a statement warning healthcare professionals not to use the chemotherapy drug Treanda Injection (bendamustine hydrochloride) with closed system transfer devices (CSTDs), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).

Now, the FDA is providing a list of devices that were tested and deemed compatible with the drug (see the tables below).

The devices were tested by Treanda’s manufacturer, Teva Pharmaceuticals.

Treanda is used to treat patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Treanda is available in 2 formulations: a solution, Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution), and a lyophilized powder, Treanda for Injection (25 mg/vial or 100 mg/vial lyophilized powder).  The information discussed here is referring to compatibility with the solution, Treanda Injection.

Treanda Injection contains N, N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA in the drug.

This incompatibility leads to device failure, such as leaking, breaking, or operational failure of CSTD components; possible product contamination; and potential serious adverse health consequences to practitioners, such as skin reactions, or to patients, including the risk of small blood vessel blockage if the product is contaminated with dissolved ABS or polycarbonate.

Users should contact device manufacturers prior to using the specific devices listed below to ensure there have been no changes made to the material composition of the devices and that the devices are compatible with Treanda use.

Table 1. The compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, and gloves (based on testing conducted by Teva from February 2015 through June 2015).

*Part numbers reflect a specific size glove used in the compatibility tests.

Table 2. The IV administration set found to be compatible with Treanda Injection after dilution in a 500 mL 0.9% sodium chloride IV infusion bags (based on testing conducted by Teva from February 2015 through June 2015*).

*Compatibility studies did not include testing with 2.5% dextrose/0.45% sodium chloride injection. However, the results of these studies are not expected to change. So either diluent, 0.9% sodium chloride or 2.5% dextrose/0.45% sodium chloride injection, can be used with Treanda injection.

The FDA required label changes for both the solution and the powder formulations of Treanda to include information for safe preparation and handling for IV administration. See the full prescribing information for details.

For more details on the compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, gloves, and IV administration sets, see Teva’s Dear Health Care Provider letter.

Adverse events or quality problems associated with the use of Treanda products can be reported to the FDA’s MedWatch Adverse Event Reporting Program.

CTL019 cells

Photo from Penn Medicine

The chimeric antigen receptor (CAR) T-cell therapy CTL019 can produce durable responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in Science Translational Medicine.

Eight of 14 patients responded to CTL019—4 complete responses (CRs) and 4 partial responses (PRs).

Three of the patients with CRs were still alive and in remission at last follow-up. The longest remission has lasted 53 months.

Only 1 patient with a PR was still alive at last follow-up, and that patient progressed.

Nine patients developed cytokine release syndrome (CRS), some requiring intensive care. And there were 2 cases of tumor lysis syndrome.

These results are the most mature data from this trial. Results from this study were previously presented at ASH 2013 and ASH 2012, and they were published in NEJM and Science Translational Medicine in August 2011.

This study was supported by grants from Novartis, the Leukemia and Lymphoma Society, and the National Institutes of Health. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

Treatment and outcomes

The trial enrolled 23 CLL patients, but only 14 received CTL019. The 14 patients had a median age of 66 (range, 51 to 78), and most (n=14) were male.

They had received a median of 5 prior therapies (range, 1 to 11), and 8 patients had 17p deletion. All patients had active disease at the time of CTL019 infusion.

Patients received CTL019 at doses of 0.14 × 10⁸ to 11 × 10⁸ cells (median, 1.6 × 10⁸ cells). Eight patients responded to the treatment, for an overall response rate of 57%.

Four patients (29%) achieved a CR. One of these patients died while in remission at 21 months due to infectious complications that occurred after removal of a basal cell carcinoma on his leg.

The other 3 CR patients remained alive at the time of analysis, with no evidence of leukemia at 28 months, 52 months, and 53 months after receiving their infusions. They did not receive additional therapy after CTL019.

“The durability of the remissions we have observed in this study are remarkable and have given us great hope that personalized cell therapies are going to be important options for patients whose cancers are no longer treatable with standard approaches,” said study author David L. Porter, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

Four patients (29%) achieved a PR after receiving CTL019, with responses lasting a median of 7 months. Two of these patients died of disease progression 10 months and 27 months after receiving CTL019.

One PR patient died after suffering a pulmonary embolism 6 months after CTL019 infusion. The last PR patient experienced disease progression at 13 months, but the patient remained alive on other therapies 36 months after receiving CTL019.

Six patients (43%) did not respond to CTL019 and progressed within 1 month to 9 months. Tests revealed that the modified T cells did not expand as robustly in these patients as in those who experienced remissions.

Two of these patients later died from their disease or complications of other therapies, and 4 are receiving other types of treatment.

CRS and other toxicity

The investigators said infusional toxicities were infrequent and mild (less than grade 2). They were primarily low-grade fevers and chills.

The most frequent related adverse events were associated with complications of neutropenia (including fevers) and delayed CRS, which was correlated with in vivo CTL019 expansion. Nine patients (including all 8 responders) developed CRS.

Five patients with CRS required anti-cytokine-directed therapy—tocilizumab (n=4) and/or steroids (n=3). Four patients required intensive care for complications related to CRS, such as hypotension and hypoxia. They remained in the intensive care unit for a median of 6 days (range, 1-9).

Concurrent with CRS were 6 neurologic events in 5 patients—grade 1/2 hallucinations, confusion, or delirium typically associated with high fevers, intensive care, or medication use. There was 1 case of grade 4 confusion that lasted 2 days and was attributed, at least partly, to CTL019.

There were 2 cases of tumor lysis syndrome. And 1 patient died in remission 21 months after CTL019 infusion, having developed overwhelming ecthyma gangrenosum from a pseudomonas wound infection from a skin biopsy site.

CTL019 durability

“Importantly, our tests of patients who experienced complete remissions showed that the modified cells remain in patients’ bodies for years after their infusions, with no sign of cancerous or normal B cells,” said study author Carl H. June, MD, of the University of Pennsylvania Perelman School of Medicine.

“This suggests that at least some of the CTL019 cells retain their ability to hunt for cancerous cells for long periods of time.”

A lab experiment using CAR T cells isolated from one of the first patients to receive CTL019 confirmed the potential for long-term function of these cells. At nearly 3 years after infusion, the patient’s CTL019 cells demonstrated immediate and specific reactivity against cells expressing CD19.

CTL019 development

The investigators did not identify demographic or disease-related factors, such as age or types of prior therapies, that could be used to predict response to CTL019. And there was no association between T-cell dose and patient response.

An ongoing dose-optimization study is exploring this relationship in greater detail. Further future areas of study may include strategies to combine CTL019 with immune checkpoint inhibitors or other therapies to stimulate T-cell recognition of tumor cells.

In addition to CLL, CTL019 is under investigation in patients with acute lymphoblastic leukemia, non-Hodgkin lymphoma, and myeloma. The product has breakthrough designation from the US Food and Drug Administration for acute lymphoblastic leukemia.

CTL019 cells

Photo from Penn Medicine

The chimeric antigen receptor (CAR) T-cell therapy CTL019 can produce durable responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in Science Translational Medicine.

Eight of 14 patients responded to CTL019—4 complete responses (CRs) and 4 partial responses (PRs).

Three of the patients with CRs were still alive and in remission at last follow-up. The longest remission has lasted 53 months.

Only 1 patient with a PR was still alive at last follow-up, and that patient progressed.

Nine patients developed cytokine release syndrome (CRS), some requiring intensive care. And there were 2 cases of tumor lysis syndrome.

These results are the most mature data from this trial. Results from this study were previously presented at ASH 2013 and ASH 2012, and they were published in NEJM and Science Translational Medicine in August 2011.

This study was supported by grants from Novartis, the Leukemia and Lymphoma Society, and the National Institutes of Health. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

Treatment and outcomes

The trial enrolled 23 CLL patients, but only 14 received CTL019. The 14 patients had a median age of 66 (range, 51 to 78), and most (n=14) were male.

They had received a median of 5 prior therapies (range, 1 to 11), and 8 patients had 17p deletion. All patients had active disease at the time of CTL019 infusion.

Patients received CTL019 at doses of 0.14 × 10⁸ to 11 × 10⁸ cells (median, 1.6 × 10⁸ cells). Eight patients responded to the treatment, for an overall response rate of 57%.

Four patients (29%) achieved a CR. One of these patients died while in remission at 21 months due to infectious complications that occurred after removal of a basal cell carcinoma on his leg.

The other 3 CR patients remained alive at the time of analysis, with no evidence of leukemia at 28 months, 52 months, and 53 months after receiving their infusions. They did not receive additional therapy after CTL019.

“The durability of the remissions we have observed in this study are remarkable and have given us great hope that personalized cell therapies are going to be important options for patients whose cancers are no longer treatable with standard approaches,” said study author David L. Porter, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

Four patients (29%) achieved a PR after receiving CTL019, with responses lasting a median of 7 months. Two of these patients died of disease progression 10 months and 27 months after receiving CTL019.

One PR patient died after suffering a pulmonary embolism 6 months after CTL019 infusion. The last PR patient experienced disease progression at 13 months, but the patient remained alive on other therapies 36 months after receiving CTL019.

Six patients (43%) did not respond to CTL019 and progressed within 1 month to 9 months. Tests revealed that the modified T cells did not expand as robustly in these patients as in those who experienced remissions.

Two of these patients later died from their disease or complications of other therapies, and 4 are receiving other types of treatment.

CRS and other toxicity

The investigators said infusional toxicities were infrequent and mild (less than grade 2). They were primarily low-grade fevers and chills.

The most frequent related adverse events were associated with complications of neutropenia (including fevers) and delayed CRS, which was correlated with in vivo CTL019 expansion. Nine patients (including all 8 responders) developed CRS.

Five patients with CRS required anti-cytokine-directed therapy—tocilizumab (n=4) and/or steroids (n=3). Four patients required intensive care for complications related to CRS, such as hypotension and hypoxia. They remained in the intensive care unit for a median of 6 days (range, 1-9).

Concurrent with CRS were 6 neurologic events in 5 patients—grade 1/2 hallucinations, confusion, or delirium typically associated with high fevers, intensive care, or medication use. There was 1 case of grade 4 confusion that lasted 2 days and was attributed, at least partly, to CTL019.

There were 2 cases of tumor lysis syndrome. And 1 patient died in remission 21 months after CTL019 infusion, having developed overwhelming ecthyma gangrenosum from a pseudomonas wound infection from a skin biopsy site.

CTL019 durability

“Importantly, our tests of patients who experienced complete remissions showed that the modified cells remain in patients’ bodies for years after their infusions, with no sign of cancerous or normal B cells,” said study author Carl H. June, MD, of the University of Pennsylvania Perelman School of Medicine.

“This suggests that at least some of the CTL019 cells retain their ability to hunt for cancerous cells for long periods of time.”

A lab experiment using CAR T cells isolated from one of the first patients to receive CTL019 confirmed the potential for long-term function of these cells. At nearly 3 years after infusion, the patient’s CTL019 cells demonstrated immediate and specific reactivity against cells expressing CD19.

CTL019 development

The investigators did not identify demographic or disease-related factors, such as age or types of prior therapies, that could be used to predict response to CTL019. And there was no association between T-cell dose and patient response.

An ongoing dose-optimization study is exploring this relationship in greater detail. Further future areas of study may include strategies to combine CTL019 with immune checkpoint inhibitors or other therapies to stimulate T-cell recognition of tumor cells.

In addition to CLL, CTL019 is under investigation in patients with acute lymphoblastic leukemia, non-Hodgkin lymphoma, and myeloma. The product has breakthrough designation from the US Food and Drug Administration for acute lymphoblastic leukemia.

CTL019 cells

Photo from Penn Medicine

The chimeric antigen receptor (CAR) T-cell therapy CTL019 can produce durable responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in Science Translational Medicine.

Eight of 14 patients responded to CTL019—4 complete responses (CRs) and 4 partial responses (PRs).

Three of the patients with CRs were still alive and in remission at last follow-up. The longest remission has lasted 53 months.

Only 1 patient with a PR was still alive at last follow-up, and that patient progressed.

Nine patients developed cytokine release syndrome (CRS), some requiring intensive care. And there were 2 cases of tumor lysis syndrome.

These results are the most mature data from this trial. Results from this study were previously presented at ASH 2013 and ASH 2012, and they were published in NEJM and Science Translational Medicine in August 2011.

This study was supported by grants from Novartis, the Leukemia and Lymphoma Society, and the National Institutes of Health. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

Treatment and outcomes

The trial enrolled 23 CLL patients, but only 14 received CTL019. The 14 patients had a median age of 66 (range, 51 to 78), and most (n=14) were male.

They had received a median of 5 prior therapies (range, 1 to 11), and 8 patients had 17p deletion. All patients had active disease at the time of CTL019 infusion.

Patients received CTL019 at doses of 0.14 × 10⁸ to 11 × 10⁸ cells (median, 1.6 × 10⁸ cells). Eight patients responded to the treatment, for an overall response rate of 57%.

Four patients (29%) achieved a CR. One of these patients died while in remission at 21 months due to infectious complications that occurred after removal of a basal cell carcinoma on his leg.

The other 3 CR patients remained alive at the time of analysis, with no evidence of leukemia at 28 months, 52 months, and 53 months after receiving their infusions. They did not receive additional therapy after CTL019.

“The durability of the remissions we have observed in this study are remarkable and have given us great hope that personalized cell therapies are going to be important options for patients whose cancers are no longer treatable with standard approaches,” said study author David L. Porter, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

Four patients (29%) achieved a PR after receiving CTL019, with responses lasting a median of 7 months. Two of these patients died of disease progression 10 months and 27 months after receiving CTL019.

One PR patient died after suffering a pulmonary embolism 6 months after CTL019 infusion. The last PR patient experienced disease progression at 13 months, but the patient remained alive on other therapies 36 months after receiving CTL019.

Six patients (43%) did not respond to CTL019 and progressed within 1 month to 9 months. Tests revealed that the modified T cells did not expand as robustly in these patients as in those who experienced remissions.

Two of these patients later died from their disease or complications of other therapies, and 4 are receiving other types of treatment.

CRS and other toxicity

The investigators said infusional toxicities were infrequent and mild (less than grade 2). They were primarily low-grade fevers and chills.

The most frequent related adverse events were associated with complications of neutropenia (including fevers) and delayed CRS, which was correlated with in vivo CTL019 expansion. Nine patients (including all 8 responders) developed CRS.

Five patients with CRS required anti-cytokine-directed therapy—tocilizumab (n=4) and/or steroids (n=3). Four patients required intensive care for complications related to CRS, such as hypotension and hypoxia. They remained in the intensive care unit for a median of 6 days (range, 1-9).

Concurrent with CRS were 6 neurologic events in 5 patients—grade 1/2 hallucinations, confusion, or delirium typically associated with high fevers, intensive care, or medication use. There was 1 case of grade 4 confusion that lasted 2 days and was attributed, at least partly, to CTL019.

There were 2 cases of tumor lysis syndrome. And 1 patient died in remission 21 months after CTL019 infusion, having developed overwhelming ecthyma gangrenosum from a pseudomonas wound infection from a skin biopsy site.

CTL019 durability

“Importantly, our tests of patients who experienced complete remissions showed that the modified cells remain in patients’ bodies for years after their infusions, with no sign of cancerous or normal B cells,” said study author Carl H. June, MD, of the University of Pennsylvania Perelman School of Medicine.

“This suggests that at least some of the CTL019 cells retain their ability to hunt for cancerous cells for long periods of time.”

A lab experiment using CAR T cells isolated from one of the first patients to receive CTL019 confirmed the potential for long-term function of these cells. At nearly 3 years after infusion, the patient’s CTL019 cells demonstrated immediate and specific reactivity against cells expressing CD19.

CTL019 development

The investigators did not identify demographic or disease-related factors, such as age or types of prior therapies, that could be used to predict response to CTL019. And there was no association between T-cell dose and patient response.

An ongoing dose-optimization study is exploring this relationship in greater detail. Further future areas of study may include strategies to combine CTL019 with immune checkpoint inhibitors or other therapies to stimulate T-cell recognition of tumor cells.

In addition to CLL, CTL019 is under investigation in patients with acute lymphoblastic leukemia, non-Hodgkin lymphoma, and myeloma. The product has breakthrough designation from the US Food and Drug Administration for acute lymphoblastic leukemia.

Burkitt lymphoma cells

Image by Ed Uthman

A link between malaria and Burkitt lymphoma was first described more than 50 years ago, but how the parasitic infection promotes lymphomagenesis has remained a mystery.

Now, research in mice has revealed that B-cell DNA becomes vulnerable to cancer-causing mutations during prolonged combat against the malaria parasite.

Davide Robbiani, MD, PhD, of The Rockefeller University in New York, New York, and his colleagues described this research in Cell.

The team infected mice with the malaria parasite Plasmodium chabaudi and, immediately, the mice experienced an increase in germinal center (GC) B lymphocytes, which can give rise to Burkitt lymphoma.

“In malaria-infected mice, these cells divide very rapidly over the course of months,” Dr Robbiani said.

As the GC B lymphocytes proliferate, they also express high levels of activation-induced cytidine deaminase (AID), which induces mutations in their DNA. As a result, these cells can diversify to generate a wide range of antibodies.

But in addition to beneficial mutations in antibody genes, AID can cause off-target damage and shuffling of cancer-causing genes.

“In mice infected with the malaria parasite, these so-called chromosomal rearrangements occur very frequently in GC lymphocytes,” Dr Robbiani said. “And at least some of the changes are due to AID.”

To further investigate this phenomenon, the researchers bred mice lacking the p53 gene, which is known to protect cells from Burkitt lymphoma. All of the mice that expressed AID but not p53 ultimately developed lymphoma.

And when these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similar to what happens in Burkitt lymphoma.

“This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other,” Dr Robbiani said.

Researchers are now attempting to determine how AID causes its off-target damage to DNA, which could lead to new treatments.

“If we could somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful,” Dr Robbiani said. “But first, we have to find out how the collateral DNA damage occurs in the first place.”

Dr Robbiani noted that hepatitis C virus and Helicobacter pylori infections, as well as some autoimmune diseases, are also linked with

chronic B lymphocyte activation and an increased risk of lymphoma.

Therefore,

strategies aimed at reducing unintended DNA damage caused by AID might

also help reduce the risk of lymphoma in patients with these conditions.

“It’s possible that AID also plays a role in the association between these other infections and cancer,” Dr Robbiani said. “This is purely a speculation at this point, though highly suggestive.”

Burkitt lymphoma cells

Image by Ed Uthman

A link between malaria and Burkitt lymphoma was first described more than 50 years ago, but how the parasitic infection promotes lymphomagenesis has remained a mystery.

Now, research in mice has revealed that B-cell DNA becomes vulnerable to cancer-causing mutations during prolonged combat against the malaria parasite.

Davide Robbiani, MD, PhD, of The Rockefeller University in New York, New York, and his colleagues described this research in Cell.

The team infected mice with the malaria parasite Plasmodium chabaudi and, immediately, the mice experienced an increase in germinal center (GC) B lymphocytes, which can give rise to Burkitt lymphoma.

“In malaria-infected mice, these cells divide very rapidly over the course of months,” Dr Robbiani said.

As the GC B lymphocytes proliferate, they also express high levels of activation-induced cytidine deaminase (AID), which induces mutations in their DNA. As a result, these cells can diversify to generate a wide range of antibodies.

But in addition to beneficial mutations in antibody genes, AID can cause off-target damage and shuffling of cancer-causing genes.

“In mice infected with the malaria parasite, these so-called chromosomal rearrangements occur very frequently in GC lymphocytes,” Dr Robbiani said. “And at least some of the changes are due to AID.”

To further investigate this phenomenon, the researchers bred mice lacking the p53 gene, which is known to protect cells from Burkitt lymphoma. All of the mice that expressed AID but not p53 ultimately developed lymphoma.

And when these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similar to what happens in Burkitt lymphoma.

“This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other,” Dr Robbiani said.

Researchers are now attempting to determine how AID causes its off-target damage to DNA, which could lead to new treatments.

“If we could somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful,” Dr Robbiani said. “But first, we have to find out how the collateral DNA damage occurs in the first place.”

Dr Robbiani noted that hepatitis C virus and Helicobacter pylori infections, as well as some autoimmune diseases, are also linked with

chronic B lymphocyte activation and an increased risk of lymphoma.

Therefore,

strategies aimed at reducing unintended DNA damage caused by AID might

also help reduce the risk of lymphoma in patients with these conditions.

“It’s possible that AID also plays a role in the association between these other infections and cancer,” Dr Robbiani said. “This is purely a speculation at this point, though highly suggestive.”

Burkitt lymphoma cells

Image by Ed Uthman

A link between malaria and Burkitt lymphoma was first described more than 50 years ago, but how the parasitic infection promotes lymphomagenesis has remained a mystery.

Now, research in mice has revealed that B-cell DNA becomes vulnerable to cancer-causing mutations during prolonged combat against the malaria parasite.

Davide Robbiani, MD, PhD, of The Rockefeller University in New York, New York, and his colleagues described this research in Cell.

The team infected mice with the malaria parasite Plasmodium chabaudi and, immediately, the mice experienced an increase in germinal center (GC) B lymphocytes, which can give rise to Burkitt lymphoma.

“In malaria-infected mice, these cells divide very rapidly over the course of months,” Dr Robbiani said.

As the GC B lymphocytes proliferate, they also express high levels of activation-induced cytidine deaminase (AID), which induces mutations in their DNA. As a result, these cells can diversify to generate a wide range of antibodies.

But in addition to beneficial mutations in antibody genes, AID can cause off-target damage and shuffling of cancer-causing genes.

“In mice infected with the malaria parasite, these so-called chromosomal rearrangements occur very frequently in GC lymphocytes,” Dr Robbiani said. “And at least some of the changes are due to AID.”

To further investigate this phenomenon, the researchers bred mice lacking the p53 gene, which is known to protect cells from Burkitt lymphoma. All of the mice that expressed AID but not p53 ultimately developed lymphoma.

And when these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similar to what happens in Burkitt lymphoma.

“This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other,” Dr Robbiani said.

Researchers are now attempting to determine how AID causes its off-target damage to DNA, which could lead to new treatments.

“If we could somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful,” Dr Robbiani said. “But first, we have to find out how the collateral DNA damage occurs in the first place.”

Dr Robbiani noted that hepatitis C virus and Helicobacter pylori infections, as well as some autoimmune diseases, are also linked with

chronic B lymphocyte activation and an increased risk of lymphoma.

Therefore,

strategies aimed at reducing unintended DNA damage caused by AID might

also help reduce the risk of lymphoma in patients with these conditions.

“It’s possible that AID also plays a role in the association between these other infections and cancer,” Dr Robbiani said. “This is purely a speculation at this point, though highly suggestive.”

 

 

Doctor and patient

Photo courtesy of NIH

 

A newly developed prognostic model can identify follicular lymphoma (FL) patients at the highest risk for treatment failure, according to researchers.

To create this model, called m7-FLIPI, the team combined the Follicular Lymphoma International Prognostic Index (FLIPI), Eastern Cooperative Oncology Group (ECOG) performance status, and the mutation status of 7 genes—EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.

The researchers said this is the first prognostic model for FL that accounts for both clinical factors and genetic mutations.

They described the creation and testing of the model in The Lancet Oncology.

“We set out to determine, at the time of diagnosis, which patients’ disease will have sustained responses after treatment and whether new genetic data could help inform which patients are at risk for developing progressive lymphoma so clinicians would be able to offer these high-risk patients more effective therapies,” said Randy Gascoyne, MD, of the British Columbia Cancer Agency in Vancouver, Canada.

He and his colleagues created the m7-FLIPI by conducting a retrospective analysis of genetic mutations and clinical risk factors in 2 cohorts of patients with symptomatic, advanced stage, or bulky FL grade 1, 2, or 3A.

The patients had a biopsy specimen collected 12 months or less before they began first-line treatment with an immunochemotherapy regimen containing rituximab.

Training cohort

The training cohort consisted of 151 FL patients who received R-CHOP. The median follow-up for these patients was 7.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found 28% of patients (43/151) were defined as high-risk, with a 5-year failure-free survival (FFS) rate of 38.29%.

And 72% of patients (108/151) were defined as low-risk, with a 5-year FFS of 77.21%. The hazard ratio was 4.14 (P<0.0001).

The positive predictive value for 5-year FFS was 64%, and the negative predictive value was 78%. The m7-FLIPI outperformed a prognostic model of only gene mutations and the FLIPI-2.

Validation cohort

The validation cohort consisted of 107 patients who received R-CVP. The median follow-up for these patients was 6.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found that 22% of patients (24/107) were defined as high-risk, with a 5-year FFS of 25%.

And 78% of patients (83/107) were defined as low-risk, with a 5-year FFS of 68.24%. The hazard ratio was 3.58 (P<0.0001).

The positive predictive value for 5-year FFS was 72%, and the negative predictive value was 68%. The m7-FLIPI outperformed the FLIPI alone and the FLIPI combined with ECOG performance status.

Overall survival

Although the m7-FLIPI was designed specifically for FFS, the researchers also tested its prognostic utility for overall survival (OS).

In the training cohort, high-risk disease according to the m7-FLIPI was associated with a 5-year OS of 65.25%, compared to 89.98% for low-risk disease (P=0.00031).

In the validation cohort, 5-year OS was 41.67% for patients with high-risk disease and 84.01% for patients with low-risk disease (P<0.0001). In both cohorts, the m7-FLIPI outperformed the FLIPI alone.

Based on these results, the researchers believe the m7-FLIPI could be utilized in a clinical setting to test all new FL patients at diagnosis and identify patients who harbor the most aggressive disease.

“The m7-FLIPI could be extremely significant for the medical community,” Dr Gascoyne said, “changing the story for high-risk patients who are currently destined to not respond well to standard treatment.”

 

 

Doctor and patient

Photo courtesy of NIH

 

A newly developed prognostic model can identify follicular lymphoma (FL) patients at the highest risk for treatment failure, according to researchers.

To create this model, called m7-FLIPI, the team combined the Follicular Lymphoma International Prognostic Index (FLIPI), Eastern Cooperative Oncology Group (ECOG) performance status, and the mutation status of 7 genes—EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.

The researchers said this is the first prognostic model for FL that accounts for both clinical factors and genetic mutations.

They described the creation and testing of the model in The Lancet Oncology.

“We set out to determine, at the time of diagnosis, which patients’ disease will have sustained responses after treatment and whether new genetic data could help inform which patients are at risk for developing progressive lymphoma so clinicians would be able to offer these high-risk patients more effective therapies,” said Randy Gascoyne, MD, of the British Columbia Cancer Agency in Vancouver, Canada.

He and his colleagues created the m7-FLIPI by conducting a retrospective analysis of genetic mutations and clinical risk factors in 2 cohorts of patients with symptomatic, advanced stage, or bulky FL grade 1, 2, or 3A.

The patients had a biopsy specimen collected 12 months or less before they began first-line treatment with an immunochemotherapy regimen containing rituximab.

Training cohort

The training cohort consisted of 151 FL patients who received R-CHOP. The median follow-up for these patients was 7.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found 28% of patients (43/151) were defined as high-risk, with a 5-year failure-free survival (FFS) rate of 38.29%.

And 72% of patients (108/151) were defined as low-risk, with a 5-year FFS of 77.21%. The hazard ratio was 4.14 (P<0.0001).

The positive predictive value for 5-year FFS was 64%, and the negative predictive value was 78%. The m7-FLIPI outperformed a prognostic model of only gene mutations and the FLIPI-2.

Validation cohort

The validation cohort consisted of 107 patients who received R-CVP. The median follow-up for these patients was 6.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found that 22% of patients (24/107) were defined as high-risk, with a 5-year FFS of 25%.

And 78% of patients (83/107) were defined as low-risk, with a 5-year FFS of 68.24%. The hazard ratio was 3.58 (P<0.0001).

The positive predictive value for 5-year FFS was 72%, and the negative predictive value was 68%. The m7-FLIPI outperformed the FLIPI alone and the FLIPI combined with ECOG performance status.

Overall survival

Although the m7-FLIPI was designed specifically for FFS, the researchers also tested its prognostic utility for overall survival (OS).

In the training cohort, high-risk disease according to the m7-FLIPI was associated with a 5-year OS of 65.25%, compared to 89.98% for low-risk disease (P=0.00031).

In the validation cohort, 5-year OS was 41.67% for patients with high-risk disease and 84.01% for patients with low-risk disease (P<0.0001). In both cohorts, the m7-FLIPI outperformed the FLIPI alone.

Based on these results, the researchers believe the m7-FLIPI could be utilized in a clinical setting to test all new FL patients at diagnosis and identify patients who harbor the most aggressive disease.

“The m7-FLIPI could be extremely significant for the medical community,” Dr Gascoyne said, “changing the story for high-risk patients who are currently destined to not respond well to standard treatment.”

 

 

Doctor and patient

Photo courtesy of NIH

 

A newly developed prognostic model can identify follicular lymphoma (FL) patients at the highest risk for treatment failure, according to researchers.

To create this model, called m7-FLIPI, the team combined the Follicular Lymphoma International Prognostic Index (FLIPI), Eastern Cooperative Oncology Group (ECOG) performance status, and the mutation status of 7 genes—EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.

The researchers said this is the first prognostic model for FL that accounts for both clinical factors and genetic mutations.

They described the creation and testing of the model in The Lancet Oncology.

“We set out to determine, at the time of diagnosis, which patients’ disease will have sustained responses after treatment and whether new genetic data could help inform which patients are at risk for developing progressive lymphoma so clinicians would be able to offer these high-risk patients more effective therapies,” said Randy Gascoyne, MD, of the British Columbia Cancer Agency in Vancouver, Canada.

He and his colleagues created the m7-FLIPI by conducting a retrospective analysis of genetic mutations and clinical risk factors in 2 cohorts of patients with symptomatic, advanced stage, or bulky FL grade 1, 2, or 3A.

The patients had a biopsy specimen collected 12 months or less before they began first-line treatment with an immunochemotherapy regimen containing rituximab.

Training cohort

The training cohort consisted of 151 FL patients who received R-CHOP. The median follow-up for these patients was 7.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found 28% of patients (43/151) were defined as high-risk, with a 5-year failure-free survival (FFS) rate of 38.29%.

And 72% of patients (108/151) were defined as low-risk, with a 5-year FFS of 77.21%. The hazard ratio was 4.14 (P<0.0001).

The positive predictive value for 5-year FFS was 64%, and the negative predictive value was 78%. The m7-FLIPI outperformed a prognostic model of only gene mutations and the FLIPI-2.

Validation cohort

The validation cohort consisted of 107 patients who received R-CVP. The median follow-up for these patients was 6.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found that 22% of patients (24/107) were defined as high-risk, with a 5-year FFS of 25%.

And 78% of patients (83/107) were defined as low-risk, with a 5-year FFS of 68.24%. The hazard ratio was 3.58 (P<0.0001).

The positive predictive value for 5-year FFS was 72%, and the negative predictive value was 68%. The m7-FLIPI outperformed the FLIPI alone and the FLIPI combined with ECOG performance status.

Overall survival

Although the m7-FLIPI was designed specifically for FFS, the researchers also tested its prognostic utility for overall survival (OS).

In the training cohort, high-risk disease according to the m7-FLIPI was associated with a 5-year OS of 65.25%, compared to 89.98% for low-risk disease (P=0.00031).

In the validation cohort, 5-year OS was 41.67% for patients with high-risk disease and 84.01% for patients with low-risk disease (P<0.0001). In both cohorts, the m7-FLIPI outperformed the FLIPI alone.

Based on these results, the researchers believe the m7-FLIPI could be utilized in a clinical setting to test all new FL patients at diagnosis and identify patients who harbor the most aggressive disease.

“The m7-FLIPI could be extremely significant for the medical community,” Dr Gascoyne said, “changing the story for high-risk patients who are currently destined to not respond well to standard treatment.”

Fabienne Mackay, PhD

Photo courtesy of

Monash University

A study published in Leukemia has revealed a mechanism by which chronic lymphocytic leukemia (CLL) evades the immune system.

“It turns out that cancer cells are very good at sabotaging the immune system, using various tricks that confuse immune cells and ‘smoke screens’ preventing immune cells from recognizing the cancer,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.

She and her colleagues believe they have determined exactly how CLL confuses the immune system and devised a way to stop it without destroying the patient’s immune system.

The team noted that B cells rely on the protein BAFF to survive. And each B cell has 3 different kinds of receptors that detect the presence of BAFF in the blood—TACI, BAFF-R, and BCMA.

The researchers discovered that, in CLL patients, the TACI receptors of cancerous B cells over-produce interleukin-10 (IL-10), which tricks the immune system into thinking nothing is wrong, allowing CLL to thrive undetected.

“We found that, when the receptor called TACI was blocked, it prevented the secretion of IL-10 without eliminating normal B cells,” Dr Mackay said. “Without IL-10, the tumor can no longer keep the immune system at bay, which means the patient’s immune system can be ‘kick-started’ again to fight infections and cancers.”

“This is very exciting because it means that B cells stay alive and well to do their job in the immune system fighting other infections. It also means the over-production of IL-10 is stopped, and the CLL cells are now exposed to immune cells specialized in fighting cancers.”

Dr Mackay said her team’s discovery may be relevant for cancers other than CLL and could change the way they are treated.

“The best weapon we have for fighting cancer is the immune system itself,” Dr Mackay noted. “It can sense the presence of an infection but also the emergence of a cancer.”

Fabienne Mackay, PhD

Photo courtesy of

Monash University

A study published in Leukemia has revealed a mechanism by which chronic lymphocytic leukemia (CLL) evades the immune system.

“It turns out that cancer cells are very good at sabotaging the immune system, using various tricks that confuse immune cells and ‘smoke screens’ preventing immune cells from recognizing the cancer,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.

She and her colleagues believe they have determined exactly how CLL confuses the immune system and devised a way to stop it without destroying the patient’s immune system.

The team noted that B cells rely on the protein BAFF to survive. And each B cell has 3 different kinds of receptors that detect the presence of BAFF in the blood—TACI, BAFF-R, and BCMA.

The researchers discovered that, in CLL patients, the TACI receptors of cancerous B cells over-produce interleukin-10 (IL-10), which tricks the immune system into thinking nothing is wrong, allowing CLL to thrive undetected.

“We found that, when the receptor called TACI was blocked, it prevented the secretion of IL-10 without eliminating normal B cells,” Dr Mackay said. “Without IL-10, the tumor can no longer keep the immune system at bay, which means the patient’s immune system can be ‘kick-started’ again to fight infections and cancers.”

“This is very exciting because it means that B cells stay alive and well to do their job in the immune system fighting other infections. It also means the over-production of IL-10 is stopped, and the CLL cells are now exposed to immune cells specialized in fighting cancers.”

Dr Mackay said her team’s discovery may be relevant for cancers other than CLL and could change the way they are treated.

“The best weapon we have for fighting cancer is the immune system itself,” Dr Mackay noted. “It can sense the presence of an infection but also the emergence of a cancer.”

Fabienne Mackay, PhD

Photo courtesy of

Monash University

A study published in Leukemia has revealed a mechanism by which chronic lymphocytic leukemia (CLL) evades the immune system.

“It turns out that cancer cells are very good at sabotaging the immune system, using various tricks that confuse immune cells and ‘smoke screens’ preventing immune cells from recognizing the cancer,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.

She and her colleagues believe they have determined exactly how CLL confuses the immune system and devised a way to stop it without destroying the patient’s immune system.

The team noted that B cells rely on the protein BAFF to survive. And each B cell has 3 different kinds of receptors that detect the presence of BAFF in the blood—TACI, BAFF-R, and BCMA.

The researchers discovered that, in CLL patients, the TACI receptors of cancerous B cells over-produce interleukin-10 (IL-10), which tricks the immune system into thinking nothing is wrong, allowing CLL to thrive undetected.

“We found that, when the receptor called TACI was blocked, it prevented the secretion of IL-10 without eliminating normal B cells,” Dr Mackay said. “Without IL-10, the tumor can no longer keep the immune system at bay, which means the patient’s immune system can be ‘kick-started’ again to fight infections and cancers.”

“This is very exciting because it means that B cells stay alive and well to do their job in the immune system fighting other infections. It also means the over-production of IL-10 is stopped, and the CLL cells are now exposed to immune cells specialized in fighting cancers.”

Dr Mackay said her team’s discovery may be relevant for cancers other than CLL and could change the way they are treated.

“The best weapon we have for fighting cancer is the immune system itself,” Dr Mackay noted. “It can sense the presence of an infection but also the emergence of a cancer.”

Micrograph showing

mycosis fungoides

Researchers have identified 15 mutations that may drive cutaneous T-cell lymphoma (CTCL).

The team sequenced normal and cancerous samples from 73 patients with mycosis fungoides or Sézary syndrome.

This revealed recurrent alterations in the TNFR2 pathway, as well as mutations in phosphoinositide 3-kinase (PI3K)-related genes, NF-κB pathway genes, and other genes that regulate T-cell survival and proliferation.

Specifically, the researchers identified TNFRSF1B point mutations, TNFRSF1B gains, CTLA4-CD28 fusions, a TRAF3 deletion, and mutations in NFAT5, TEC, PIK3CD, PIK3R6, PIK3CG, PIK3R5, PIK3R4, VAV1, MALT1, CD28, and ITK.

Paul Khavari, MD, PhD, of Stanford University in California, and his colleagues conducted this research and described their findings in a letter to Nature Genetics.

TNFR2 mutations

The researchers noted that the most frequent recurrent point mutation they identified occurred at codon 377 of TNFRSF1B (5%; 4/73), resulting in a recurrent TNFR2 Thr377Ile mutant.

TNFR2 is a receptor that regulates T-cell signaling pathways, and the mutation locked the receptor into an always-on state, preventing the T-cell-survival pathway from shutting down.

Previous studies showed that patients with increased TNFR2 in their bloodstream had more aggressive forms of CTCL that were more likely to return quickly after treatment.

This led Dr Khavari and his colleagues to look at the other patients’ DNA to see if duplications could account for both the elevated levels in the blood and increased signaling to activate the T-cell-survival pathway. The team found that 10 of the patients had TNFRSF1B gains.

In total, TNFRSF1B was altered in 18% of patients (13/73), by point mutation or gain (both in 1 patient). The researchers said this suggests a potential role of oncogenic TNFR2 signaling in the development of CTCL.

The team uncovered evidence to support this role by growing cells in the lab with either the point mutation or the gain. Their experiment showed the T-cell-survival pathway was more active in these cells than in normal cells.

Now, the researchers are working to incorporate the mutations they identified into the DNA of mice to study the mutated genes’ effects and the actions of drugs on those genes.

Micrograph showing

mycosis fungoides

Researchers have identified 15 mutations that may drive cutaneous T-cell lymphoma (CTCL).

The team sequenced normal and cancerous samples from 73 patients with mycosis fungoides or Sézary syndrome.

This revealed recurrent alterations in the TNFR2 pathway, as well as mutations in phosphoinositide 3-kinase (PI3K)-related genes, NF-κB pathway genes, and other genes that regulate T-cell survival and proliferation.

Specifically, the researchers identified TNFRSF1B point mutations, TNFRSF1B gains, CTLA4-CD28 fusions, a TRAF3 deletion, and mutations in NFAT5, TEC, PIK3CD, PIK3R6, PIK3CG, PIK3R5, PIK3R4, VAV1, MALT1, CD28, and ITK.

Paul Khavari, MD, PhD, of Stanford University in California, and his colleagues conducted this research and described their findings in a letter to Nature Genetics.

TNFR2 mutations

The researchers noted that the most frequent recurrent point mutation they identified occurred at codon 377 of TNFRSF1B (5%; 4/73), resulting in a recurrent TNFR2 Thr377Ile mutant.

TNFR2 is a receptor that regulates T-cell signaling pathways, and the mutation locked the receptor into an always-on state, preventing the T-cell-survival pathway from shutting down.

Previous studies showed that patients with increased TNFR2 in their bloodstream had more aggressive forms of CTCL that were more likely to return quickly after treatment.

This led Dr Khavari and his colleagues to look at the other patients’ DNA to see if duplications could account for both the elevated levels in the blood and increased signaling to activate the T-cell-survival pathway. The team found that 10 of the patients had TNFRSF1B gains.

In total, TNFRSF1B was altered in 18% of patients (13/73), by point mutation or gain (both in 1 patient). The researchers said this suggests a potential role of oncogenic TNFR2 signaling in the development of CTCL.

The team uncovered evidence to support this role by growing cells in the lab with either the point mutation or the gain. Their experiment showed the T-cell-survival pathway was more active in these cells than in normal cells.

Now, the researchers are working to incorporate the mutations they identified into the DNA of mice to study the mutated genes’ effects and the actions of drugs on those genes.

Micrograph showing

mycosis fungoides

Researchers have identified 15 mutations that may drive cutaneous T-cell lymphoma (CTCL).

The team sequenced normal and cancerous samples from 73 patients with mycosis fungoides or Sézary syndrome.

This revealed recurrent alterations in the TNFR2 pathway, as well as mutations in phosphoinositide 3-kinase (PI3K)-related genes, NF-κB pathway genes, and other genes that regulate T-cell survival and proliferation.

Specifically, the researchers identified TNFRSF1B point mutations, TNFRSF1B gains, CTLA4-CD28 fusions, a TRAF3 deletion, and mutations in NFAT5, TEC, PIK3CD, PIK3R6, PIK3CG, PIK3R5, PIK3R4, VAV1, MALT1, CD28, and ITK.

Paul Khavari, MD, PhD, of Stanford University in California, and his colleagues conducted this research and described their findings in a letter to Nature Genetics.

TNFR2 mutations

The researchers noted that the most frequent recurrent point mutation they identified occurred at codon 377 of TNFRSF1B (5%; 4/73), resulting in a recurrent TNFR2 Thr377Ile mutant.

TNFR2 is a receptor that regulates T-cell signaling pathways, and the mutation locked the receptor into an always-on state, preventing the T-cell-survival pathway from shutting down.

Previous studies showed that patients with increased TNFR2 in their bloodstream had more aggressive forms of CTCL that were more likely to return quickly after treatment.

This led Dr Khavari and his colleagues to look at the other patients’ DNA to see if duplications could account for both the elevated levels in the blood and increased signaling to activate the T-cell-survival pathway. The team found that 10 of the patients had TNFRSF1B gains.

In total, TNFRSF1B was altered in 18% of patients (13/73), by point mutation or gain (both in 1 patient). The researchers said this suggests a potential role of oncogenic TNFR2 signaling in the development of CTCL.

The team uncovered evidence to support this role by growing cells in the lab with either the point mutation or the gain. Their experiment showed the T-cell-survival pathway was more active in these cells than in normal cells.

Now, the researchers are working to incorporate the mutations they identified into the DNA of mice to study the mutated genes’ effects and the actions of drugs on those genes.

An untreated lesion pre-

treatment (top) and 16 weeks

after treatment began

Photo from Penn Medicine

Results of a phase 1 trial suggest a topical gel can prompt regression of both treated and untreated lesions in patients with

early stage cutaneous T-cell lymphoma (CTCL).

Of the 12 patients who received the treatment, resiquimod gel, 75% had a significant improvement in treated lesions.

And 92% of patients had a more than 50% improvement in body surface area involvement, which included untreated lesions. Two patients experienced complete disease clearance.

Adverse events associated with resiquimod were largely limited to the skin, although 2 patients had transient, low-grade fever. Five patients developed superficial skin erosions that healed when treatment was stopped and did not reappear after treatment began again.

Alain Rook, MD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these results in Blood.

“The results of the trial suggest that resiquimod is safely and effectively absorbed into the skin and, beyond diminishing treated lesions, also enhances the immune response, leading to healing of even untreated lesions,” Dr Rook said.

“To our knowledge, this is the first topical therapy that can clear untreated lesions and lead to complete remission in some patients.”

Treatment and response

Dr Rook and his colleagues tested resiquimod gel in 12 patients who had previously undergone an average of 6 treatments for early stage CTCL.

The patients applied specified doses of resiquimod (0.03% or 0.06%) to select skin lesions for 16 weeks. Some patients using the 0.06% dose had complete clearance of all malignant cells after 8 weeks.

By the final evaluation, treated lesions had significantly improved in 75% of patients, and 30% of patients had complete clearance of all treated lesions.

Resiquimod also improved untreated lesions, resulting in more than 50% improvement in body surface area involvement for 92% of patients.

Two participants, one of whom had been living with CTCL for more than 15 years without responding to treatment, experienced complete eradication of the disease.

Malignant cell analysis

The researchers used high-throughput sequencing to detect malignant cells in patient samples. The technique could identify a single malignant cell among 100,000 healthy cells.

The team analyzed DNA from biopsies of the same lesion before treatment and 8 weeks after treatment began.

They observed a significant reduction of malignant T cells in 9 of 10 patients tested, 3 of whom had complete eradication of the malignant population and 1 of whom had a 99.6% reduction.

Adverse events

Adverse events associated with resiquimod were all grade 1 and were primarily related to local skin irritation. There were no serious adverse events.

Five of 8 patients receiving resiquimod at the 0.06% dose developed superficial skin erosions at some sites of treatment. These erosions healed completely within a week of stopping treatment and did not recur with re-initiation of treatment.

Two patients receiving the 0.06% dose experienced 2 days of low-grade fever (less than 100.50 F) when treatment began.

“Overall, lesions responded far better to topical resiquimod than they have with other topical therapies, including some potent topical steroids and topical chemotherapy, and [resiquimod] was extremely well tolerated by patients,” Dr Rook said.

“Building upon previous research, our study suggests resiquimod might be useful in combination with other therapies in the treatment of more advanced CTCL. Further research with larger participant populations is needed to determine the best approach and application for these patients.”

An untreated lesion pre-

treatment (top) and 16 weeks

after treatment began

Photo from Penn Medicine

Results of a phase 1 trial suggest a topical gel can prompt regression of both treated and untreated lesions in patients with

early stage cutaneous T-cell lymphoma (CTCL).

Of the 12 patients who received the treatment, resiquimod gel, 75% had a significant improvement in treated lesions.

And 92% of patients had a more than 50% improvement in body surface area involvement, which included untreated lesions. Two patients experienced complete disease clearance.

Adverse events associated with resiquimod were largely limited to the skin, although 2 patients had transient, low-grade fever. Five patients developed superficial skin erosions that healed when treatment was stopped and did not reappear after treatment began again.

Alain Rook, MD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these results in Blood.

“The results of the trial suggest that resiquimod is safely and effectively absorbed into the skin and, beyond diminishing treated lesions, also enhances the immune response, leading to healing of even untreated lesions,” Dr Rook said.

“To our knowledge, this is the first topical therapy that can clear untreated lesions and lead to complete remission in some patients.”

Treatment and response

Dr Rook and his colleagues tested resiquimod gel in 12 patients who had previously undergone an average of 6 treatments for early stage CTCL.

The patients applied specified doses of resiquimod (0.03% or 0.06%) to select skin lesions for 16 weeks. Some patients using the 0.06% dose had complete clearance of all malignant cells after 8 weeks.

By the final evaluation, treated lesions had significantly improved in 75% of patients, and 30% of patients had complete clearance of all treated lesions.

Resiquimod also improved untreated lesions, resulting in more than 50% improvement in body surface area involvement for 92% of patients.

Two participants, one of whom had been living with CTCL for more than 15 years without responding to treatment, experienced complete eradication of the disease.

Malignant cell analysis

The researchers used high-throughput sequencing to detect malignant cells in patient samples. The technique could identify a single malignant cell among 100,000 healthy cells.

The team analyzed DNA from biopsies of the same lesion before treatment and 8 weeks after treatment began.

They observed a significant reduction of malignant T cells in 9 of 10 patients tested, 3 of whom had complete eradication of the malignant population and 1 of whom had a 99.6% reduction.

Adverse events

Adverse events associated with resiquimod were all grade 1 and were primarily related to local skin irritation. There were no serious adverse events.

Five of 8 patients receiving resiquimod at the 0.06% dose developed superficial skin erosions at some sites of treatment. These erosions healed completely within a week of stopping treatment and did not recur with re-initiation of treatment.

Two patients receiving the 0.06% dose experienced 2 days of low-grade fever (less than 100.50 F) when treatment began.

“Overall, lesions responded far better to topical resiquimod than they have with other topical therapies, including some potent topical steroids and topical chemotherapy, and [resiquimod] was extremely well tolerated by patients,” Dr Rook said.

“Building upon previous research, our study suggests resiquimod might be useful in combination with other therapies in the treatment of more advanced CTCL. Further research with larger participant populations is needed to determine the best approach and application for these patients.”

An untreated lesion pre-

treatment (top) and 16 weeks

after treatment began

Photo from Penn Medicine

Results of a phase 1 trial suggest a topical gel can prompt regression of both treated and untreated lesions in patients with

early stage cutaneous T-cell lymphoma (CTCL).

Of the 12 patients who received the treatment, resiquimod gel, 75% had a significant improvement in treated lesions.

And 92% of patients had a more than 50% improvement in body surface area involvement, which included untreated lesions. Two patients experienced complete disease clearance.

Adverse events associated with resiquimod were largely limited to the skin, although 2 patients had transient, low-grade fever. Five patients developed superficial skin erosions that healed when treatment was stopped and did not reappear after treatment began again.

Alain Rook, MD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these results in Blood.

“The results of the trial suggest that resiquimod is safely and effectively absorbed into the skin and, beyond diminishing treated lesions, also enhances the immune response, leading to healing of even untreated lesions,” Dr Rook said.

“To our knowledge, this is the first topical therapy that can clear untreated lesions and lead to complete remission in some patients.”

Treatment and response

Dr Rook and his colleagues tested resiquimod gel in 12 patients who had previously undergone an average of 6 treatments for early stage CTCL.

The patients applied specified doses of resiquimod (0.03% or 0.06%) to select skin lesions for 16 weeks. Some patients using the 0.06% dose had complete clearance of all malignant cells after 8 weeks.

By the final evaluation, treated lesions had significantly improved in 75% of patients, and 30% of patients had complete clearance of all treated lesions.

Resiquimod also improved untreated lesions, resulting in more than 50% improvement in body surface area involvement for 92% of patients.

Two participants, one of whom had been living with CTCL for more than 15 years without responding to treatment, experienced complete eradication of the disease.

Malignant cell analysis

The researchers used high-throughput sequencing to detect malignant cells in patient samples. The technique could identify a single malignant cell among 100,000 healthy cells.

The team analyzed DNA from biopsies of the same lesion before treatment and 8 weeks after treatment began.

They observed a significant reduction of malignant T cells in 9 of 10 patients tested, 3 of whom had complete eradication of the malignant population and 1 of whom had a 99.6% reduction.

Adverse events

Adverse events associated with resiquimod were all grade 1 and were primarily related to local skin irritation. There were no serious adverse events.

Five of 8 patients receiving resiquimod at the 0.06% dose developed superficial skin erosions at some sites of treatment. These erosions healed completely within a week of stopping treatment and did not recur with re-initiation of treatment.

Two patients receiving the 0.06% dose experienced 2 days of low-grade fever (less than 100.50 F) when treatment began.

“Overall, lesions responded far better to topical resiquimod than they have with other topical therapies, including some potent topical steroids and topical chemotherapy, and [resiquimod] was extremely well tolerated by patients,” Dr Rook said.

“Building upon previous research, our study suggests resiquimod might be useful in combination with other therapies in the treatment of more advanced CTCL. Further research with larger participant populations is needed to determine the best approach and application for these patients.”