Non-Hodgkin Lymphoma

Micrograph showing CTCL

The US Food and Drug Administration (FDA) has granted orphan drug designation to TLC178 for the treatment of cutaneous T-cell lymphoma (CTCL).

TLC178 is a liposomal-encapsulated formulation of the chemotherapy drug vinorelbine, which is FDA approved to treat non-small cell lung cancer.

The goal with TLC178 is to improve the efficacy and decrease the toxicity of vinorelbine to extend the indication beyond solid tumors into lymphoma.

A proprietary technology known as NanoX™ is used to load vinorelbine into liposomes designed to target tumor-specific cell-surface epitopes, extend the circulation time of the drug, increase the concentation of drug delivered to tumor cells, and decrease side effects.

TLC178 is being developed by Taiwan Liposome Company.

The company recently received US FDA approval for its phase 1/2 study (NCT02925000) investigating TLC178 in patients with advanced cancers, including CTCL and other lymphomas.

This trial is planned for sites in Taiwan and the US. The trial will be initiated in Taiwan once approval is granted by the Taiwan FDA.

About orphan designation

The US FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing CTCL

The US Food and Drug Administration (FDA) has granted orphan drug designation to TLC178 for the treatment of cutaneous T-cell lymphoma (CTCL).

TLC178 is a liposomal-encapsulated formulation of the chemotherapy drug vinorelbine, which is FDA approved to treat non-small cell lung cancer.

The goal with TLC178 is to improve the efficacy and decrease the toxicity of vinorelbine to extend the indication beyond solid tumors into lymphoma.

A proprietary technology known as NanoX™ is used to load vinorelbine into liposomes designed to target tumor-specific cell-surface epitopes, extend the circulation time of the drug, increase the concentation of drug delivered to tumor cells, and decrease side effects.

TLC178 is being developed by Taiwan Liposome Company.

The company recently received US FDA approval for its phase 1/2 study (NCT02925000) investigating TLC178 in patients with advanced cancers, including CTCL and other lymphomas.

This trial is planned for sites in Taiwan and the US. The trial will be initiated in Taiwan once approval is granted by the Taiwan FDA.

About orphan designation

The US FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing CTCL

The US Food and Drug Administration (FDA) has granted orphan drug designation to TLC178 for the treatment of cutaneous T-cell lymphoma (CTCL).

TLC178 is a liposomal-encapsulated formulation of the chemotherapy drug vinorelbine, which is FDA approved to treat non-small cell lung cancer.

The goal with TLC178 is to improve the efficacy and decrease the toxicity of vinorelbine to extend the indication beyond solid tumors into lymphoma.

A proprietary technology known as NanoX™ is used to load vinorelbine into liposomes designed to target tumor-specific cell-surface epitopes, extend the circulation time of the drug, increase the concentation of drug delivered to tumor cells, and decrease side effects.

TLC178 is being developed by Taiwan Liposome Company.

The company recently received US FDA approval for its phase 1/2 study (NCT02925000) investigating TLC178 in patients with advanced cancers, including CTCL and other lymphomas.

This trial is planned for sites in Taiwan and the US. The trial will be initiated in Taiwan once approval is granted by the Taiwan FDA.

About orphan designation

The US FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Steven Treon, MD, PhD
Photo courtesy of DFCI

NEW YORK—Whole-genome sequencing has changed the entire approach to drug development for Waldenström’s macroglobulinemia (WM), according to a speaker at Lymphoma & Myeloma 2016.

The strategy has changed from a hand-me-down one, relying on drugs developed first for other diseases, to a rational plan designed specifically to treat WM patients. 

“We would wait for our colleagues in the myeloma world or lymphoma world, CLL world, anywhere we could find them, to help us with the development of drugs,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts. 

“And, sometimes, this resulted in delays of many, many years before those therapeutics could be vetted out and eventually be handed down to the Waldenström investigators.”

At Lymphoma & Myeloma 2016, Dr Treon described the current therapy of WM and the impact of the discovery of MYD88 and CXCR4 on drug development and treatment choices in WM.

Rituximab-based therapy

WM is a disease that strongly expresses CD20, even though it’s a lymphoplasmacytic disease. So rituximab, given alone and in combination, has been, to date, the most common approach to treating WM.

As a single agent, rituximab produces a response in 25% to 40% of WM patients, but these are very seldom deep responses, Dr Treon noted.

So investigators combined rituximab with cyclophosphamide, nucleoside analogues, proteasome inhibitors, and bendamustine, which increased the overall response rate and depth of response. 

This translated into improvement in time to progression, which is now 4 to 5 years with these combination therapies.

“Now, the problem is, when you borrow things from other people, you sometimes end up with problems you didn’t anticipate,” Dr Treon said. 

One of the unanticipated side effects with rituximab in WM patients is the IgM flare, which occurs in 40% to 60% of WM patients. 

Rituximab can also cause hypogammaglobulinema, leading to infections, and results in a high intolerance rate, which tends to occur a few cycles into induction or maintenance therapy. 

“In some cases,” Dr Treon advised, “a switch to ofatumumab, a fully human CD20 molecule, overcomes this intolerance.”

Nucleoside analogues, which used to be the mainstay of WM, have a high rate of transformation into a more aggressive lymphoma or acute myeloid leukemia.

Immunomodulatory drugs, particularly thalidomide, cause peripheral neuropathy greater than grade 2 in 60% of patients.

And a greater incidence of peripheral neuropathy is also observed with proteasome inhibitors, particularly bortezomib, in WM patients than in myeloma or mantle cell lymphoma patients.

“So this was at least the impetus for why we needed to develop novel approaches to treating this disease,” Dr Treon said.

MYD88 mutations

With whole-genome sequencing, investigators discovered that mutations in the MYD88 gene were highly prevalent in WM patients.

About 93% to 95% of WM patients have the L265P MYD88 mutation, and about 2% have the non-L265P MYD88 mutation. 

MYD88 has prognostic significance in WM. Mutated MYD88 confers a better prognosis than unmutated MYD88.

MYD88 may also be important in predicting who will respond to drugs like ibrutinib.

CXCR4 mutations

Mutations in CXCR4 are the second most common mutation in WM. 

Between 30% and 40% of WM patients have the WHIM-like CXCR4 C-tail mutations, which traffic the Waldenström’s cells to the bone marrow.

This mutation promotes drug resistance, including resistance to ibrutinib because of the enhanced AKT/ERK signaling. 

Ibrutinib therapy 

With this in mind, investigators set out to evaluate the potential of using a BTK inhibitor in relapsed/refractory WM patients and at the same time observe the genomics that might predict for response and resistance. 

They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.

Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.

“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.” 

The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort. 

The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).

The progression-free survival at 2 years was 69% and overall survival was 95%. 

At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia. 

And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated. 

Response to ibrutinib by mutation status

The overall response rate was 90% for all patients, but there were differences according to mutation status. 

Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.

Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well. 

If they also had a CXCR4^WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%. 

“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.

Patients with a CXCR4 mutation also respond more slowly than those without the mutation.

This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.

“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said. 

“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.” 

Ibrutinib in rituximab-refractory patients

A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.

The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.

Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.

Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.

The study was just accepted for publication in Lancet Oncology.

IRAK inhibition

Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.

So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.

Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.

“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”  

Resistance to ibrutinib 

Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds. 

These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation. 

C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.

So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.

Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase. 

Other drugs being developed for WM include:

• Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
• Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
  
• Agents that block CXCR4 receptor signaling, such as ulocuplomab
• The BCL2 inhibitor venetoclax
• The CD38-targeted agent daratumumab.

Current treatment strategies

Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.

For patients with mutated MYD88 and no CXCR4 mutation:

• If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
• If patients have bulky disease, a combination of bendamustine and rituximab may be used. 
• If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
• If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.

For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions. 

To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib. 

The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.

“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”

Bendamustine- or bortezomib-based therapy is effective in this population and can be considered. 

In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.

Steven Treon, MD, PhD
Photo courtesy of DFCI

NEW YORK—Whole-genome sequencing has changed the entire approach to drug development for Waldenström’s macroglobulinemia (WM), according to a speaker at Lymphoma & Myeloma 2016.

The strategy has changed from a hand-me-down one, relying on drugs developed first for other diseases, to a rational plan designed specifically to treat WM patients. 

“We would wait for our colleagues in the myeloma world or lymphoma world, CLL world, anywhere we could find them, to help us with the development of drugs,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts. 

“And, sometimes, this resulted in delays of many, many years before those therapeutics could be vetted out and eventually be handed down to the Waldenström investigators.”

At Lymphoma & Myeloma 2016, Dr Treon described the current therapy of WM and the impact of the discovery of MYD88 and CXCR4 on drug development and treatment choices in WM.

Rituximab-based therapy

WM is a disease that strongly expresses CD20, even though it’s a lymphoplasmacytic disease. So rituximab, given alone and in combination, has been, to date, the most common approach to treating WM.

As a single agent, rituximab produces a response in 25% to 40% of WM patients, but these are very seldom deep responses, Dr Treon noted.

So investigators combined rituximab with cyclophosphamide, nucleoside analogues, proteasome inhibitors, and bendamustine, which increased the overall response rate and depth of response. 

This translated into improvement in time to progression, which is now 4 to 5 years with these combination therapies.

“Now, the problem is, when you borrow things from other people, you sometimes end up with problems you didn’t anticipate,” Dr Treon said. 

One of the unanticipated side effects with rituximab in WM patients is the IgM flare, which occurs in 40% to 60% of WM patients. 

Rituximab can also cause hypogammaglobulinema, leading to infections, and results in a high intolerance rate, which tends to occur a few cycles into induction or maintenance therapy. 

“In some cases,” Dr Treon advised, “a switch to ofatumumab, a fully human CD20 molecule, overcomes this intolerance.”

Nucleoside analogues, which used to be the mainstay of WM, have a high rate of transformation into a more aggressive lymphoma or acute myeloid leukemia.

Immunomodulatory drugs, particularly thalidomide, cause peripheral neuropathy greater than grade 2 in 60% of patients.

And a greater incidence of peripheral neuropathy is also observed with proteasome inhibitors, particularly bortezomib, in WM patients than in myeloma or mantle cell lymphoma patients.

“So this was at least the impetus for why we needed to develop novel approaches to treating this disease,” Dr Treon said.

MYD88 mutations

With whole-genome sequencing, investigators discovered that mutations in the MYD88 gene were highly prevalent in WM patients.

About 93% to 95% of WM patients have the L265P MYD88 mutation, and about 2% have the non-L265P MYD88 mutation. 

MYD88 has prognostic significance in WM. Mutated MYD88 confers a better prognosis than unmutated MYD88.

MYD88 may also be important in predicting who will respond to drugs like ibrutinib.

CXCR4 mutations

Mutations in CXCR4 are the second most common mutation in WM. 

Between 30% and 40% of WM patients have the WHIM-like CXCR4 C-tail mutations, which traffic the Waldenström’s cells to the bone marrow.

This mutation promotes drug resistance, including resistance to ibrutinib because of the enhanced AKT/ERK signaling. 

Ibrutinib therapy 

With this in mind, investigators set out to evaluate the potential of using a BTK inhibitor in relapsed/refractory WM patients and at the same time observe the genomics that might predict for response and resistance. 

They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.

Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.

“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.” 

The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort. 

The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).

The progression-free survival at 2 years was 69% and overall survival was 95%. 

At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia. 

And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated. 

Response to ibrutinib by mutation status

The overall response rate was 90% for all patients, but there were differences according to mutation status. 

Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.

Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well. 

If they also had a CXCR4^WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%. 

“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.

Patients with a CXCR4 mutation also respond more slowly than those without the mutation.

This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.

“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said. 

“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.” 

Ibrutinib in rituximab-refractory patients

A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.

The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.

Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.

Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.

The study was just accepted for publication in Lancet Oncology.

IRAK inhibition

Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.

So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.

Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.

“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”  

Resistance to ibrutinib 

Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds. 

These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation. 

C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.

So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.

Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase. 

Other drugs being developed for WM include:

• Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
• Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
  
• Agents that block CXCR4 receptor signaling, such as ulocuplomab
• The BCL2 inhibitor venetoclax
• The CD38-targeted agent daratumumab.

Current treatment strategies

Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.

For patients with mutated MYD88 and no CXCR4 mutation:

• If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
• If patients have bulky disease, a combination of bendamustine and rituximab may be used. 
• If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
• If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.

For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions. 

To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib. 

The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.

“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”

Bendamustine- or bortezomib-based therapy is effective in this population and can be considered. 

In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.

Steven Treon, MD, PhD
Photo courtesy of DFCI

NEW YORK—Whole-genome sequencing has changed the entire approach to drug development for Waldenström’s macroglobulinemia (WM), according to a speaker at Lymphoma & Myeloma 2016.

The strategy has changed from a hand-me-down one, relying on drugs developed first for other diseases, to a rational plan designed specifically to treat WM patients. 

“We would wait for our colleagues in the myeloma world or lymphoma world, CLL world, anywhere we could find them, to help us with the development of drugs,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts. 

“And, sometimes, this resulted in delays of many, many years before those therapeutics could be vetted out and eventually be handed down to the Waldenström investigators.”

At Lymphoma & Myeloma 2016, Dr Treon described the current therapy of WM and the impact of the discovery of MYD88 and CXCR4 on drug development and treatment choices in WM.

Rituximab-based therapy

WM is a disease that strongly expresses CD20, even though it’s a lymphoplasmacytic disease. So rituximab, given alone and in combination, has been, to date, the most common approach to treating WM.

As a single agent, rituximab produces a response in 25% to 40% of WM patients, but these are very seldom deep responses, Dr Treon noted.

So investigators combined rituximab with cyclophosphamide, nucleoside analogues, proteasome inhibitors, and bendamustine, which increased the overall response rate and depth of response. 

This translated into improvement in time to progression, which is now 4 to 5 years with these combination therapies.

“Now, the problem is, when you borrow things from other people, you sometimes end up with problems you didn’t anticipate,” Dr Treon said. 

One of the unanticipated side effects with rituximab in WM patients is the IgM flare, which occurs in 40% to 60% of WM patients. 

Rituximab can also cause hypogammaglobulinema, leading to infections, and results in a high intolerance rate, which tends to occur a few cycles into induction or maintenance therapy. 

“In some cases,” Dr Treon advised, “a switch to ofatumumab, a fully human CD20 molecule, overcomes this intolerance.”

Nucleoside analogues, which used to be the mainstay of WM, have a high rate of transformation into a more aggressive lymphoma or acute myeloid leukemia.

Immunomodulatory drugs, particularly thalidomide, cause peripheral neuropathy greater than grade 2 in 60% of patients.

And a greater incidence of peripheral neuropathy is also observed with proteasome inhibitors, particularly bortezomib, in WM patients than in myeloma or mantle cell lymphoma patients.

“So this was at least the impetus for why we needed to develop novel approaches to treating this disease,” Dr Treon said.

MYD88 mutations

With whole-genome sequencing, investigators discovered that mutations in the MYD88 gene were highly prevalent in WM patients.

About 93% to 95% of WM patients have the L265P MYD88 mutation, and about 2% have the non-L265P MYD88 mutation. 

MYD88 has prognostic significance in WM. Mutated MYD88 confers a better prognosis than unmutated MYD88.

MYD88 may also be important in predicting who will respond to drugs like ibrutinib.

CXCR4 mutations

Mutations in CXCR4 are the second most common mutation in WM. 

Between 30% and 40% of WM patients have the WHIM-like CXCR4 C-tail mutations, which traffic the Waldenström’s cells to the bone marrow.

This mutation promotes drug resistance, including resistance to ibrutinib because of the enhanced AKT/ERK signaling. 

Ibrutinib therapy 

With this in mind, investigators set out to evaluate the potential of using a BTK inhibitor in relapsed/refractory WM patients and at the same time observe the genomics that might predict for response and resistance. 

They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.

Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.

“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.” 

The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort. 

The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).

The progression-free survival at 2 years was 69% and overall survival was 95%. 

At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia. 

And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated. 

Response to ibrutinib by mutation status

The overall response rate was 90% for all patients, but there were differences according to mutation status. 

Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.

Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well. 

If they also had a CXCR4^WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%. 

“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.

Patients with a CXCR4 mutation also respond more slowly than those without the mutation.

This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.

“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said. 

“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.” 

Ibrutinib in rituximab-refractory patients

A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.

The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.

Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.

Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.

The study was just accepted for publication in Lancet Oncology.

IRAK inhibition

Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.

So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.

Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.

“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”  

Resistance to ibrutinib 

Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds. 

These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation. 

C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.

So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.

Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase. 

Other drugs being developed for WM include:

• Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
• Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
  
• Agents that block CXCR4 receptor signaling, such as ulocuplomab
• The BCL2 inhibitor venetoclax
• The CD38-targeted agent daratumumab.

Current treatment strategies

Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.

For patients with mutated MYD88 and no CXCR4 mutation:

• If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
• If patients have bulky disease, a combination of bendamustine and rituximab may be used. 
• If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
• If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.

For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions. 

To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib. 

The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.

“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”

Bendamustine- or bortezomib-based therapy is effective in this population and can be considered. 

In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.

Burkitt lymphoma

Image by Ed Uthman

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

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

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

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

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

About S63845

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

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

In hematologic malignancies, S63845 proved effective when given alone.

Myeloma

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

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

Lymphoma

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

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

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

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

Leukemia

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

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

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

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

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

Development/funding

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

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

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

Burkitt lymphoma

Image by Ed Uthman

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

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

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

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

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

About S63845

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

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

In hematologic malignancies, S63845 proved effective when given alone.

Myeloma

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

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

Lymphoma

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

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

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

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

Leukemia

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

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

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

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

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

Development/funding

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

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

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

Burkitt lymphoma

Image by Ed Uthman

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

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

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

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

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

About S63845

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

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

In hematologic malignancies, S63845 proved effective when given alone.

Myeloma

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

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

Lymphoma

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

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

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

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

Leukemia

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

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

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

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

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

Development/funding

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

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

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

Cancer patient receives therapy

Photo by Rhoda Baer

A new study suggests that leukemia and non-Hodgkin lymphoma (NHL) are among the top 10 cancers with the greatest burden (most years of healthy life lost) in the US.

The research also showed that the burden of different cancer types varied between patients belonging to different racial/ethnic groups.

For example, the contribution of leukemia to the overall cancer burden was twice as high in Hispanics as it was in non-Hispanic blacks. The same was true for NHL.

Joannie Lortet-Tieulent, of the American Cancer Society in Atlanta, Georgia, and her colleagues conducted this study and reported the results in the American Journal of Preventive Medicine.

The researchers calculated the burden of cancer in the US in 2011 for 24 cancer types. They calculated burden using disability-adjusted life years (DALYs), which combine cancer incidence, mortality, survival, and quality of life into a summary indicator.

The results suggested the burden of cancer in 2011 was over 9.8 million DALYs, which was equally shared between men and women—4.9 million DALYs for each sex.

DALYs lost to cancer were mostly related to premature death due to cancer (91%). The remaining 9% were related to impaired quality of life because of the disease or its treatment, or other disease-related issues.

Top 10 contributors

The researchers calculated the proportion of DALYs lost for each of the cancer types. And they found that lung cancer was the largest contributor to the loss of healthy years, accounting for 24% of the burden (2.4 million DALYs).

The second biggest contributor to the loss of healthy years was breast cancer (10%), followed by colorectal cancer (9%), pancreatic cancer (6%), prostate cancer (5%), leukemia (4%), liver cancer (4%), brain cancer (3%), NHL (3%), and ovarian cancer (3%).

The researchers also calculated the proportion of DALYs lost from the top 10 cancer types according to race/ethnicity.

They found the contribution of leukemia to the loss of healthy years was greatest for Hispanics (6%), followed by non-Hispanic Asians (5%), non-Hispanic whites (4%), and non-Hispanic blacks (3%).

The contribution of NHL to the loss of healthy years was greatest for Hispanics (4%), followed by non-Hispanic Asians/non-Hispanic whites (3% for both), and non-Hispanic blacks (2%).

DALYs by race/ethnicity

The researchers found that, overall, the cancer burden was highest in non-Hispanic blacks, followed by non-Hispanic whites, Hispanics, and non-Hispanic Asians. However, this pattern was not consistent across the different cancer types.

Age-standardized DALYs lost (per 100,000 individuals) were as follows:

All cancers combined

3588 for non-Hispanic blacks

2898 for non-Hispanic whites

1978 for Hispanics

1798 for non-Hispanic Asians.

Leukemia

115 for non-Hispanic blacks and non-Hispanic whites

98 for Hispanics

82 for non-Hispanic Asians.

NHL

93 for non-Hispanic whites

86 for non-Hispanic blacks

78 for Hispanics

60 for non-Hispanic Asians.

Hodgkin lymphoma

11 for non-Hispanic blacks

10 for non-Hispanic whites and Hispanics

3 for non-Hispanic Asians.

Myeloma

93 for non-Hispanic blacks

43 for non-Hispanic whites

42 for Hispanics

26 for non-Hispanic Asians.

The researchers noted that, despite these differences, the cancer burden in all races/ethnicities was driven by years of life lost. They said this highlights the need to prevent deaths by improving prevention, early detection, and treatment of cancers.

Cancer patient receives therapy

Photo by Rhoda Baer

A new study suggests that leukemia and non-Hodgkin lymphoma (NHL) are among the top 10 cancers with the greatest burden (most years of healthy life lost) in the US.

The research also showed that the burden of different cancer types varied between patients belonging to different racial/ethnic groups.

For example, the contribution of leukemia to the overall cancer burden was twice as high in Hispanics as it was in non-Hispanic blacks. The same was true for NHL.

Joannie Lortet-Tieulent, of the American Cancer Society in Atlanta, Georgia, and her colleagues conducted this study and reported the results in the American Journal of Preventive Medicine.

The researchers calculated the burden of cancer in the US in 2011 for 24 cancer types. They calculated burden using disability-adjusted life years (DALYs), which combine cancer incidence, mortality, survival, and quality of life into a summary indicator.

The results suggested the burden of cancer in 2011 was over 9.8 million DALYs, which was equally shared between men and women—4.9 million DALYs for each sex.

DALYs lost to cancer were mostly related to premature death due to cancer (91%). The remaining 9% were related to impaired quality of life because of the disease or its treatment, or other disease-related issues.

Top 10 contributors

The researchers calculated the proportion of DALYs lost for each of the cancer types. And they found that lung cancer was the largest contributor to the loss of healthy years, accounting for 24% of the burden (2.4 million DALYs).

The second biggest contributor to the loss of healthy years was breast cancer (10%), followed by colorectal cancer (9%), pancreatic cancer (6%), prostate cancer (5%), leukemia (4%), liver cancer (4%), brain cancer (3%), NHL (3%), and ovarian cancer (3%).

The researchers also calculated the proportion of DALYs lost from the top 10 cancer types according to race/ethnicity.

They found the contribution of leukemia to the loss of healthy years was greatest for Hispanics (6%), followed by non-Hispanic Asians (5%), non-Hispanic whites (4%), and non-Hispanic blacks (3%).

The contribution of NHL to the loss of healthy years was greatest for Hispanics (4%), followed by non-Hispanic Asians/non-Hispanic whites (3% for both), and non-Hispanic blacks (2%).

DALYs by race/ethnicity

The researchers found that, overall, the cancer burden was highest in non-Hispanic blacks, followed by non-Hispanic whites, Hispanics, and non-Hispanic Asians. However, this pattern was not consistent across the different cancer types.

Age-standardized DALYs lost (per 100,000 individuals) were as follows:

All cancers combined

3588 for non-Hispanic blacks

2898 for non-Hispanic whites

1978 for Hispanics

1798 for non-Hispanic Asians.

Leukemia

115 for non-Hispanic blacks and non-Hispanic whites

98 for Hispanics

82 for non-Hispanic Asians.

NHL

93 for non-Hispanic whites

86 for non-Hispanic blacks

78 for Hispanics

60 for non-Hispanic Asians.

Hodgkin lymphoma

11 for non-Hispanic blacks

10 for non-Hispanic whites and Hispanics

3 for non-Hispanic Asians.

Myeloma

93 for non-Hispanic blacks

43 for non-Hispanic whites

42 for Hispanics

26 for non-Hispanic Asians.

The researchers noted that, despite these differences, the cancer burden in all races/ethnicities was driven by years of life lost. They said this highlights the need to prevent deaths by improving prevention, early detection, and treatment of cancers.

Cancer patient receives therapy

Photo by Rhoda Baer

A new study suggests that leukemia and non-Hodgkin lymphoma (NHL) are among the top 10 cancers with the greatest burden (most years of healthy life lost) in the US.

The research also showed that the burden of different cancer types varied between patients belonging to different racial/ethnic groups.

For example, the contribution of leukemia to the overall cancer burden was twice as high in Hispanics as it was in non-Hispanic blacks. The same was true for NHL.

Joannie Lortet-Tieulent, of the American Cancer Society in Atlanta, Georgia, and her colleagues conducted this study and reported the results in the American Journal of Preventive Medicine.

The researchers calculated the burden of cancer in the US in 2011 for 24 cancer types. They calculated burden using disability-adjusted life years (DALYs), which combine cancer incidence, mortality, survival, and quality of life into a summary indicator.

The results suggested the burden of cancer in 2011 was over 9.8 million DALYs, which was equally shared between men and women—4.9 million DALYs for each sex.

DALYs lost to cancer were mostly related to premature death due to cancer (91%). The remaining 9% were related to impaired quality of life because of the disease or its treatment, or other disease-related issues.

Top 10 contributors

The researchers calculated the proportion of DALYs lost for each of the cancer types. And they found that lung cancer was the largest contributor to the loss of healthy years, accounting for 24% of the burden (2.4 million DALYs).

The second biggest contributor to the loss of healthy years was breast cancer (10%), followed by colorectal cancer (9%), pancreatic cancer (6%), prostate cancer (5%), leukemia (4%), liver cancer (4%), brain cancer (3%), NHL (3%), and ovarian cancer (3%).

The researchers also calculated the proportion of DALYs lost from the top 10 cancer types according to race/ethnicity.

They found the contribution of leukemia to the loss of healthy years was greatest for Hispanics (6%), followed by non-Hispanic Asians (5%), non-Hispanic whites (4%), and non-Hispanic blacks (3%).

The contribution of NHL to the loss of healthy years was greatest for Hispanics (4%), followed by non-Hispanic Asians/non-Hispanic whites (3% for both), and non-Hispanic blacks (2%).

DALYs by race/ethnicity

The researchers found that, overall, the cancer burden was highest in non-Hispanic blacks, followed by non-Hispanic whites, Hispanics, and non-Hispanic Asians. However, this pattern was not consistent across the different cancer types.

Age-standardized DALYs lost (per 100,000 individuals) were as follows:

All cancers combined

3588 for non-Hispanic blacks

2898 for non-Hispanic whites

1978 for Hispanics

1798 for non-Hispanic Asians.

Leukemia

115 for non-Hispanic blacks and non-Hispanic whites

98 for Hispanics

82 for non-Hispanic Asians.

NHL

93 for non-Hispanic whites

86 for non-Hispanic blacks

78 for Hispanics

60 for non-Hispanic Asians.

Hodgkin lymphoma

11 for non-Hispanic blacks

10 for non-Hispanic whites and Hispanics

3 for non-Hispanic Asians.

Myeloma

93 for non-Hispanic blacks

43 for non-Hispanic whites

42 for Hispanics

26 for non-Hispanic Asians.

The researchers noted that, despite these differences, the cancer burden in all races/ethnicities was driven by years of life lost. They said this highlights the need to prevent deaths by improving prevention, early detection, and treatment of cancers.

CLL cells

Researchers say they have found a better way to examine individual cells, and this tool provided insight that could inform the treatment of leukemia.

The team used a technique called microarrayed single-cell sequencing (MASC-seq) to examine individual cells in samples from patients with chronic lymphocytic leukemia (CLL).

This revealed a number of CLL subclones within each sample that exhibited different gene expression.

“With this new, highly cost-effective technology, we can now get a whole new view of this complexity within the blood cancer sample,” said study author Joakim Lundeberg, PhD, of KTH Royal Institute of Technology in Stockholm, Sweden.

“Molecular resolution of single cells is likely to become a more widely used therapy option.”

Dr Lundeberg and his colleagues described this work in Nature Communications.

The researchers said current methods of single-cell analysis don’t allow for the combination of cell imaging and transcriptome profiling, exhibit low-throughput by analyzing a single cell at a time, or require expensive droplet instrumentation for high-throughput analysis.

MASC-seq, on the other hand, can image cells to provide information on morphology and profile the expression of thousands of single cells per day at a cost of $0.13 USD per cell.

Dr Lundeberg and his colleagues tested MASC-seq by analyzing samples from 3 patients with different subtypes of CLL.

The team found clear differences in the average gene expression levels of cells from the different CLL subtypes, but they also found subtle differences between single cells within each of the subtypes.

The researchers therefore concluded that MASC-seq has the potential to accelerate the study of subtle clonal dynamics and help provide insight into the development of CLL and other diseases.

CLL cells

Researchers say they have found a better way to examine individual cells, and this tool provided insight that could inform the treatment of leukemia.

The team used a technique called microarrayed single-cell sequencing (MASC-seq) to examine individual cells in samples from patients with chronic lymphocytic leukemia (CLL).

This revealed a number of CLL subclones within each sample that exhibited different gene expression.

“With this new, highly cost-effective technology, we can now get a whole new view of this complexity within the blood cancer sample,” said study author Joakim Lundeberg, PhD, of KTH Royal Institute of Technology in Stockholm, Sweden.

“Molecular resolution of single cells is likely to become a more widely used therapy option.”

Dr Lundeberg and his colleagues described this work in Nature Communications.

The researchers said current methods of single-cell analysis don’t allow for the combination of cell imaging and transcriptome profiling, exhibit low-throughput by analyzing a single cell at a time, or require expensive droplet instrumentation for high-throughput analysis.

MASC-seq, on the other hand, can image cells to provide information on morphology and profile the expression of thousands of single cells per day at a cost of $0.13 USD per cell.

Dr Lundeberg and his colleagues tested MASC-seq by analyzing samples from 3 patients with different subtypes of CLL.

The team found clear differences in the average gene expression levels of cells from the different CLL subtypes, but they also found subtle differences between single cells within each of the subtypes.

The researchers therefore concluded that MASC-seq has the potential to accelerate the study of subtle clonal dynamics and help provide insight into the development of CLL and other diseases.

CLL cells

Researchers say they have found a better way to examine individual cells, and this tool provided insight that could inform the treatment of leukemia.

The team used a technique called microarrayed single-cell sequencing (MASC-seq) to examine individual cells in samples from patients with chronic lymphocytic leukemia (CLL).

This revealed a number of CLL subclones within each sample that exhibited different gene expression.

“With this new, highly cost-effective technology, we can now get a whole new view of this complexity within the blood cancer sample,” said study author Joakim Lundeberg, PhD, of KTH Royal Institute of Technology in Stockholm, Sweden.

“Molecular resolution of single cells is likely to become a more widely used therapy option.”

Dr Lundeberg and his colleagues described this work in Nature Communications.

The researchers said current methods of single-cell analysis don’t allow for the combination of cell imaging and transcriptome profiling, exhibit low-throughput by analyzing a single cell at a time, or require expensive droplet instrumentation for high-throughput analysis.

MASC-seq, on the other hand, can image cells to provide information on morphology and profile the expression of thousands of single cells per day at a cost of $0.13 USD per cell.

Dr Lundeberg and his colleagues tested MASC-seq by analyzing samples from 3 patients with different subtypes of CLL.

The team found clear differences in the average gene expression levels of cells from the different CLL subtypes, but they also found subtle differences between single cells within each of the subtypes.

The researchers therefore concluded that MASC-seq has the potential to accelerate the study of subtle clonal dynamics and help provide insight into the development of CLL and other diseases.

The CAR T-cell therapy CTL019

Photo from Penn Medicine

NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.

Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.

Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.

“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.

He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.

Pilot study of CTL019 in CLL

CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.

The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.

Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.

Two patients in this trial are still in CR beyond 5 years.

When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.

First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.

Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.

“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”

Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.

“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”

“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”

Dose-finding trial of CTL019 in CLL

The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.

The high-dose arm (5x10⁸ CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x10⁷ CTL019).

Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.

Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.

Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.

With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.

“Toxicities were identical in each group,” Dr Schuster said.

He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.

There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.

So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.

Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.

“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”

Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”

Toxicity of CTL019 in CLL

“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”

Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.

B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.

“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”

In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.

Other CAR T-cell trials in CLL

Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.

“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.

Combination trials with ibrutinib

Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”

So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.

A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.

“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”

The CAR T-cell therapy CTL019

Photo from Penn Medicine

NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.

Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.

Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.

“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.

He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.

Pilot study of CTL019 in CLL

CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.

The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.

Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.

Two patients in this trial are still in CR beyond 5 years.

When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.

First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.

Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.

“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”

Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.

“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”

“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”

Dose-finding trial of CTL019 in CLL

The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.

The high-dose arm (5x10⁸ CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x10⁷ CTL019).

Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.

Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.

Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.

With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.

“Toxicities were identical in each group,” Dr Schuster said.

He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.

There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.

So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.

Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.

“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”

Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”

Toxicity of CTL019 in CLL

“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”

Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.

B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.

“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”

In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.

Other CAR T-cell trials in CLL

Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.

“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.

Combination trials with ibrutinib

Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”

So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.

A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.

“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”

The CAR T-cell therapy CTL019

Photo from Penn Medicine

NEW YORK—Trial data on the use of chimeric antigen receptor (CAR) T cells in chronic lymphocytic leukemia (CLL) are maturing, and a speaker at Lymphoma & Myeloma 2016 provided some perspective on the therapy as it now stands.

Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, noted that some CLL patients treated with CAR T cells remain in complete remission (CR) for more than 5 years.

Therefore, CAR T cells may be a consideration for patients who are resistant to chemotherapy.

“[I]mportantly, this immunologic approach, like other immunologic approaches . . ., tends to be non-cross-resistant to chemotherapy,” Dr Schuster said.

He made these and other observations while discussing trials of CAR T-cell therapy (particularly CTL019) in CLL.

Pilot study of CTL019 in CLL

CTL019, which is the CAR T-cell therapy used by investigators at the University of Pennsylvania, is licensed to Novartis.

The pilot study of CTL019, begun in 2009, enrolled 14 patients who had failed at least 2 prior therapies and progressed within 2 years of their last treatment.

Four patients (29%) achieved a CR, and 4 (29%) achieved a partial response (PR), for an overall response rate of 57%. Detailed results from this trial were reported earlier in HematologyTimes.

Two patients in this trial are still in CR beyond 5 years.

When investigators analyzed the different variables that might affect response—including age, number of prior therapies, p53 status, CAR T-cell dose, and the presence of cytokine release syndrome (CRS)—2 things became apparent.

First, patients who responded tended to have greater in vivo expansion of the CAR T cells than non-responders. And second, the responders had a greater incidence of CRS than non-responders.

Additionally, complete responders were negative for minimal residual disease (MRD) and had durable responses.

“This actually is different from the data you see in lymphoma with CAR cells,” Dr Schuster said. “[However,] it’s what we see in ALL [acute lymphoblastic leukemia] as well.”

Investigators also discovered that persistence of CAR T cells correlates with B-cell aplasia. In this trial, persistence of CAR T cells and B-cell aplasia were apparent at 12 and 18 months, and, in some cases, even longer.

“This is in distinction to what we are observing in trials with the lymphomas,” Dr Schuster said. “So what’s going to emerge is that the different diseases will have different response rates, different degrees of persistence of CAR cells and different toxicities.”

“When we compare B-cell ALL, B-cell non-Hodgkin lymphomas, you’ll get different responses across the subtypes of lymphomas, some unique toxicities, and differences in CLL. So these are all different diseases.”

Dose-finding trial of CTL019 in CLL

The second trial of CTL019 in relapsed/refractory CLL patients was a dose-finding study. Updated results from this study were presented at ASCO 2016.

The high-dose arm (5x10⁸ CTL019) had a 10 times higher dose of CAR T cells than the low-dose arm (5x10⁷ CTL019).

Investigators treated 12 patients in each arm in the first phase of the study, and then expanded the trial to include another 8 patients at the recommended dose. The phase 2 trial was powered for response rates but not duration of response.

Twenty-eight patients were enrolled, with 24 evaluable, 11 in the high-dose arm and 13 in the low-dose arm.

Their median age was 62 (range, 51-75), the median number of prior therapies was 4 (range, 2–7), 38% had p53 deletion, and 12% had received prior ibrutinib therapy.

With the 2 arms pooled together, 25% of patients achieved a CR, and 17% achieved a PR, for an overall response rate of 42%.

“Toxicities were identical in each group,” Dr Schuster said.

He noted that the CRS rate was “fairly high.” The incidence was 55% in the high-dose arm and 54% in the low-dose arm.

There was a tendency, although not statistically significant, for the higher-dose patients to have a greater response rate than the lower-dose group—54% and 31%, respectively.

So the investigators decided the expansion cohort should be conducted with the higher dose, “even though we weren’t sure there really was a difference,” Dr Schuster said.

Seventeen evaluable patients received the higher dose in the expansion cohort. Six (35%) achieved a CR, and 3 (18%) achieved a PR, for an overall response rate of 53%.

“Most [adverse] events happen in the first 3 months,” after infusion, Dr Schuster said. “And then nothing much happens. That’s because the patients that are responsive to this therapy have durable responses.”

Of all the patients who achieved a CR, only 2 have relapsed, he said, “and now many of these patients have passed the 5-year mark for complete remissions.”

Toxicity of CTL019 in CLL

“When you give the cells, there’s not much toxicity,” Dr Schuster said. “These are the patients’ own cells; they’re not reacting adversely to that. It’s what happens afterwards that you have to be on the lookout for as the cells begin to expand in vivo.”

Patients experience some reversible renal toxicity, mostly hypertension-related, and some tumor lysis syndrome (TLS). No deaths occurred from TLS in CLL.

B-cell aplasia and hypogammaglobulinema occur in responding patients. They receive gamma globulin replacement as supportive therapy and generally experience no excessive or unusual infections.

“Cytokine release syndrome is the real thing to look at,” Dr Schuster said, “and that’s where early recognition and management will be life-saving.”

In both CLL and ALL, almost all responding patients develop CRS, which can be rapidly reversed with tocilizumab, the IL-6 receptor blocker.

Other CAR T-cell trials in CLL

Institutions other than the University of Pennsylvania have conducted trials of CAR T-cell therapies other than CTL019, and response rates in CLL patients have ranged from 25% (MSKCC) to 46% (Seattle), as reported at ASCO this year.

“But what’s really important to keep in mind is almost all patients who achieve complete response to date have stayed in complete response,” Dr Schuster said.

Combination trials with ibrutinib

Dr Schuster noted that patients in CAR T-cell trials who had been on ibrutinib for more than 5 months “had really robust T-cell expansion.”

So investigators believe treatment with ibrutinib may be a way of enhancing T-cell function.

A combination trial of ibrutinib and CTL019 is underway (NCT02640209). Six patients have been treated thus far, and although the follow-up is short, all 6 achieved CR at the 3-month assessment.

“So the hope is that this is going to be a partner [therapy],” Dr Schuster said. “And maybe these complete responses will be very durable, like the responses in earlier trials of CAR therapy in patients with CLL.”

Micrograph showing CLL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of venetoclax (Venclyxto™).

The CHMP is recommending that venetoclax receive conditional marketing authorization to treat adults with chronic lymphocytic leukemia (CLL) who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with an inhibitor of the B-cell receptor pathway.

The CHMP is also recommending the conditional authorization of venetoclax as a treatment for adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemo immunotherapy and treatment with an inhibitor of the B-cell receptor pathway.

The European Commission (EC) will review the CHMP’s opinion and is expected to make a final decision about venetoclax in late 2016.

If the EC follows the CHMP’s recommendations, venetoclax will become the first BCL-2 inhibitor approved for use in Europe. The authorization will be valid in all member states of the European Union, as well as Iceland, Liechtenstein, and Norway.

Conditional marketing authorization represents an expedited path for approval. The EC grants conditional marketing authorization to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.

Conditional marketing authorization is granted before pivotal registration studies of a product are completed, but the company developing the product is required to complete post-marketing studies showing that the product provides a clinical benefit.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Venetoclax is currently approved for use in Argentina, Canada, Puerto Rico, and the US. The drug is being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Phase 2 trial

Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.

Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.

At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.

Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.

At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

The incidence of serious adverse events was 55%. The most common of these were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

Micrograph showing CLL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of venetoclax (Venclyxto™).

The CHMP is recommending that venetoclax receive conditional marketing authorization to treat adults with chronic lymphocytic leukemia (CLL) who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with an inhibitor of the B-cell receptor pathway.

The CHMP is also recommending the conditional authorization of venetoclax as a treatment for adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemo immunotherapy and treatment with an inhibitor of the B-cell receptor pathway.

The European Commission (EC) will review the CHMP’s opinion and is expected to make a final decision about venetoclax in late 2016.

If the EC follows the CHMP’s recommendations, venetoclax will become the first BCL-2 inhibitor approved for use in Europe. The authorization will be valid in all member states of the European Union, as well as Iceland, Liechtenstein, and Norway.

Conditional marketing authorization represents an expedited path for approval. The EC grants conditional marketing authorization to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.

Conditional marketing authorization is granted before pivotal registration studies of a product are completed, but the company developing the product is required to complete post-marketing studies showing that the product provides a clinical benefit.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Venetoclax is currently approved for use in Argentina, Canada, Puerto Rico, and the US. The drug is being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Phase 2 trial

Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.

Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.

At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.

Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.

At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

The incidence of serious adverse events was 55%. The most common of these were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

Micrograph showing CLL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of venetoclax (Venclyxto™).

The CHMP is recommending that venetoclax receive conditional marketing authorization to treat adults with chronic lymphocytic leukemia (CLL) who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with an inhibitor of the B-cell receptor pathway.

The CHMP is also recommending the conditional authorization of venetoclax as a treatment for adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemo immunotherapy and treatment with an inhibitor of the B-cell receptor pathway.

The European Commission (EC) will review the CHMP’s opinion and is expected to make a final decision about venetoclax in late 2016.

If the EC follows the CHMP’s recommendations, venetoclax will become the first BCL-2 inhibitor approved for use in Europe. The authorization will be valid in all member states of the European Union, as well as Iceland, Liechtenstein, and Norway.

Conditional marketing authorization represents an expedited path for approval. The EC grants conditional marketing authorization to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.

Conditional marketing authorization is granted before pivotal registration studies of a product are completed, but the company developing the product is required to complete post-marketing studies showing that the product provides a clinical benefit.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Venetoclax is currently approved for use in Argentina, Canada, Puerto Rico, and the US. The drug is being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Phase 2 trial

Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.

Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.

At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.

Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.

At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

The incidence of serious adverse events was 55%. The most common of these were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

Andrew Zelenetz, MD, PhD

NEW YORK—The importance of cell of origin in choosing a treatment for diffuse large B-cell lymphoma (DLBCL) is a topic “that has been kicking around for 16 years,” according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.

Cell of origin was first described in the year 2000 as a distinguishing factor in large-cell lymphoma, said the speaker, Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York.

The cell of origin in DLBCL—whether it’s germinal center B cell (GCB), activated B cell (ABC), or unclassified—contributes to biological and clinical heterogeneity of the disease.

“And more importantly, activated B-cell diffuse large B-cell lymphoma and germinal center diffuse large B-cell lymphoma are simply different diseases,” Dr Zelenetz said.

He then elaborated on the importance of cell of origin in treating DLBCL.

Biology

Dr Zelenetz noted that ABC and GCB lymphomas have different molecular pathways. ABC lymphomas are very dependent on the NF-kB pathway and have more active signaling through the B-cell receptor.

The GCB lymphomas tend to have more tonic regulation, and the PI3 kinase/mTOR pathway is more critical. GCB lymphomas have more genomic instability.

“So cell of origin determination identifies tumors with distinct biology, may provide prognostic information, and may be predictive for treatment selection,” Dr Zelenetz said. “Unfortunately, cell of origin is not the whole story.” 

Gene mutations occur in large-cell lymphoma “just like every other cancer,” Dr Zelenetz said. And the vast majority occur in both lymphoma subtypes, he added, further complicating our understanding of the biology of these tumors.

Some of these mutations predict for sensitivity to treatment, while others predict for resistance. For example, CARD11 predicts for resistance to ibrutinib, while CD79b predicts for sensitivity.

Determining the cell of origin

Gene-expression profiling on fresh tissue is considered the gold standard, but “it is clearly not a clinical tool,” Dr Zelenetz said.  It requires the Wright classifier, a statistical method based on Bayes’ rule, to make patient-level assignments to 1 of the 3 subgroups.

Immunohistochemistry is widely available, but reproducibility may be difficult. Many assays exist, such as the Hans, Choi, and Muris assays, but, in many studies, there may be a lack of correlation with gene-expression profiling.

In the last few years, gene-expression profiling of formalin‐fixed paraffin‐embedded (FFPE) tissue has emerged as a reliable method. The assay is reproducible between laboratories, and it’s reproducible between different sets of reagents.

“[T]here is tremendous correlation between the Lymph2Cx assay and the gold standard,” Dr Zelenetz added.

“So here we have a robust assay,” he said, which allows investigators to explore whether the cell of origin is prognostic in large-cell lymphoma.

Prognosis

In a data set of 339 patients with de novo DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the Lymph2Cx assay showing cell of origin was predictive of overall and progression-free survival.

However, the same exact assay applied to the RICOVER-60 data from the German High-Grade Non-Hodgkin Lymphoma Study group was not predictive, Dr Zelenetz reported, based on a personal communication from one of the investigators. There was a slight trend in favor of GCB tumors, but it was not statistically significant.

And the REMoDL-B study, using gene-expression profiling of FFPE tissue with the DASL assay, also didn’t show any difference in outcome between ABC or GCB tumors.

So gene-expression profiling of FFPE tissue does not universally show a prognostic difference, Dr Zelenetz said.

Influence of chemotherapy by cell of origin

CALGB 59910 showed that GCB tumors had a superior event-free, progression-free, and overall survival with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) compared to ABC tumors.

“However, this is a phase 2, hypothesis-generating experiment,” Dr Zelenetz pointed out, and the results of the confirmatory study comparing dose-adjusted EPOCH-R and R-CHOP21 (CALGB 50303) will be presented later this year at the ASH Annual Meeting.

Sequential, non-cross-resistant chemotherapy

Data from the Memorial Sloan Kettering study (MSKCC 01-142/08-146; NCT00712582) of sequential therapy with R-CHOP followed by ICE (ifosfamide, carboplatin, and etoposide) demonstrate “excellent” progression-free and overall survival, Dr Zelenetz said.

“When we analyzed the outcome by cell of origin, there was a suggestion that the patients with the non-germinal center tumors were actually doing better than the germinal center tumors,” he added.

He pointed out one of the limitations of the study is that the cell of origin was determined by the Hans model. Nevertheless, the study raised another testable hypothesis: sequential therapy might overcome the adverse impact of the non-germinal center tumors.

Cell of origin analysis of the prospective, randomized study (LNH 03-2B) comparing R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) to R-CHOP showed that whether patients with GCB tumors received CHOP or ACVBP didn’t make “a whit of difference,” Dr Zelenetz said, in terms of progression-free and overall survival.

However, patients with ABC tumors demonstrated an “enormous difference in favor of R-ACVBP,” he said.

“Again, evidence that you can overcome the adverse effect of the ABC tumors with chemotherapy.”

Dr Zelenetz pointed out that R-ACVBP and R-CHOP followed by ICE are “actually remarkably similar regimens.” Both are sequential, both include consolidation, and both incorporate high-dose ifosfamide and etoposide.

“[S]o they actually reinforce each other,” he said, “demonstrating a similar result.”

Lenalidomide

Lenalidomide in the relapsed/refractory setting has modest activity in DLBCL, with most of the benefit accruing to patients with non-germinal center tumors.

Two clinical studies evaluated the impact of adding lenalidomide to standard chemotherapy.

In an Italian series using lenalidomide (L) plus R-CHOP21 in elderly untreated patients, the combination produced outstanding progression-free and event-free survival, but with no significant differences between the subtypes.

A US study of RL-CHOP versus R-CHOP included 87 matched historical controls treated with R-CHOP and 64 patients treated with RL-CHOP. Patients with non-germinal center tumors treated with RL-CHOP fared much better than historical controls treated with R-CHOP.

However, among germinal center tumors, “there was not a hint of any difference,” Dr Zelenetz noted.

Two studies—E1412, using an unselected population, and the international ROBUST study, selecting for patients with ABC tumors—are underway to confirm that the benefit with lenalidomide is in patients with activated B-cell tumors.

Ibrutinib

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, also has modest activity as a single agent in an unselected patient population with relapsed/refractory DLBCL. And most of the patients who demonstrated benefit had activated B-cell tumors.

Upon further analysis, investigators found that response was enhanced by the CD79b mutation, but it was not necessary for a response. And patients with CARD11 had no response.

MYD88 mutations seemed to cause resistance to ibrutinib, unless the mutation was associated with the CD79b mutation, and then patients had a “great” response, Dr Zelenetz explained.

In the upfront setting, a phase 1b study of R-CHOP plus ibrutinib demonstrated the safety of the combination, which had an overall survival rate of 100% and a complete response rate of 91%.

The prospective, randomized, phase 3 PHOENIX trial (NCT01855750) evaluating the combination in newly diagnosed non-germinal center DLBCL has completed accrual, but analysis is still pending.

Conclusion

“The prognostic significance of cell of origin is still controversial,” Dr Zelenetz wrapped up, “although I actually believe there is a prognostic difference in unselected registry patients.”

Sequential chemotherapy with ifosfamide and etoposide consolidation does very well in activated B-cell tumors, both in phase 2 and phase 3 studies.

“Importantly, small molecules seem to have differential effects totally predictable based on the biology of the difference between activated B-cell and germinal center tumors,” Dr Zelenetz said.

“But the big wild card here is somatic mutations further complicate things and will have to be incorporated into our understanding in the selection of patients.”

Andrew Zelenetz, MD, PhD

NEW YORK—The importance of cell of origin in choosing a treatment for diffuse large B-cell lymphoma (DLBCL) is a topic “that has been kicking around for 16 years,” according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.

Cell of origin was first described in the year 2000 as a distinguishing factor in large-cell lymphoma, said the speaker, Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York.

The cell of origin in DLBCL—whether it’s germinal center B cell (GCB), activated B cell (ABC), or unclassified—contributes to biological and clinical heterogeneity of the disease.

“And more importantly, activated B-cell diffuse large B-cell lymphoma and germinal center diffuse large B-cell lymphoma are simply different diseases,” Dr Zelenetz said.

He then elaborated on the importance of cell of origin in treating DLBCL.

Biology

Dr Zelenetz noted that ABC and GCB lymphomas have different molecular pathways. ABC lymphomas are very dependent on the NF-kB pathway and have more active signaling through the B-cell receptor.

The GCB lymphomas tend to have more tonic regulation, and the PI3 kinase/mTOR pathway is more critical. GCB lymphomas have more genomic instability.

“So cell of origin determination identifies tumors with distinct biology, may provide prognostic information, and may be predictive for treatment selection,” Dr Zelenetz said. “Unfortunately, cell of origin is not the whole story.” 

Gene mutations occur in large-cell lymphoma “just like every other cancer,” Dr Zelenetz said. And the vast majority occur in both lymphoma subtypes, he added, further complicating our understanding of the biology of these tumors.

Some of these mutations predict for sensitivity to treatment, while others predict for resistance. For example, CARD11 predicts for resistance to ibrutinib, while CD79b predicts for sensitivity.

Determining the cell of origin

Gene-expression profiling on fresh tissue is considered the gold standard, but “it is clearly not a clinical tool,” Dr Zelenetz said.  It requires the Wright classifier, a statistical method based on Bayes’ rule, to make patient-level assignments to 1 of the 3 subgroups.

Immunohistochemistry is widely available, but reproducibility may be difficult. Many assays exist, such as the Hans, Choi, and Muris assays, but, in many studies, there may be a lack of correlation with gene-expression profiling.

In the last few years, gene-expression profiling of formalin‐fixed paraffin‐embedded (FFPE) tissue has emerged as a reliable method. The assay is reproducible between laboratories, and it’s reproducible between different sets of reagents.

“[T]here is tremendous correlation between the Lymph2Cx assay and the gold standard,” Dr Zelenetz added.

“So here we have a robust assay,” he said, which allows investigators to explore whether the cell of origin is prognostic in large-cell lymphoma.

Prognosis

In a data set of 339 patients with de novo DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the Lymph2Cx assay showing cell of origin was predictive of overall and progression-free survival.

However, the same exact assay applied to the RICOVER-60 data from the German High-Grade Non-Hodgkin Lymphoma Study group was not predictive, Dr Zelenetz reported, based on a personal communication from one of the investigators. There was a slight trend in favor of GCB tumors, but it was not statistically significant.

And the REMoDL-B study, using gene-expression profiling of FFPE tissue with the DASL assay, also didn’t show any difference in outcome between ABC or GCB tumors.

So gene-expression profiling of FFPE tissue does not universally show a prognostic difference, Dr Zelenetz said.

Influence of chemotherapy by cell of origin

CALGB 59910 showed that GCB tumors had a superior event-free, progression-free, and overall survival with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) compared to ABC tumors.

“However, this is a phase 2, hypothesis-generating experiment,” Dr Zelenetz pointed out, and the results of the confirmatory study comparing dose-adjusted EPOCH-R and R-CHOP21 (CALGB 50303) will be presented later this year at the ASH Annual Meeting.

Sequential, non-cross-resistant chemotherapy

Data from the Memorial Sloan Kettering study (MSKCC 01-142/08-146; NCT00712582) of sequential therapy with R-CHOP followed by ICE (ifosfamide, carboplatin, and etoposide) demonstrate “excellent” progression-free and overall survival, Dr Zelenetz said.

“When we analyzed the outcome by cell of origin, there was a suggestion that the patients with the non-germinal center tumors were actually doing better than the germinal center tumors,” he added.

He pointed out one of the limitations of the study is that the cell of origin was determined by the Hans model. Nevertheless, the study raised another testable hypothesis: sequential therapy might overcome the adverse impact of the non-germinal center tumors.

Cell of origin analysis of the prospective, randomized study (LNH 03-2B) comparing R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) to R-CHOP showed that whether patients with GCB tumors received CHOP or ACVBP didn’t make “a whit of difference,” Dr Zelenetz said, in terms of progression-free and overall survival.

However, patients with ABC tumors demonstrated an “enormous difference in favor of R-ACVBP,” he said.

“Again, evidence that you can overcome the adverse effect of the ABC tumors with chemotherapy.”

Dr Zelenetz pointed out that R-ACVBP and R-CHOP followed by ICE are “actually remarkably similar regimens.” Both are sequential, both include consolidation, and both incorporate high-dose ifosfamide and etoposide.

“[S]o they actually reinforce each other,” he said, “demonstrating a similar result.”

Lenalidomide

Lenalidomide in the relapsed/refractory setting has modest activity in DLBCL, with most of the benefit accruing to patients with non-germinal center tumors.

Two clinical studies evaluated the impact of adding lenalidomide to standard chemotherapy.

In an Italian series using lenalidomide (L) plus R-CHOP21 in elderly untreated patients, the combination produced outstanding progression-free and event-free survival, but with no significant differences between the subtypes.

A US study of RL-CHOP versus R-CHOP included 87 matched historical controls treated with R-CHOP and 64 patients treated with RL-CHOP. Patients with non-germinal center tumors treated with RL-CHOP fared much better than historical controls treated with R-CHOP.

However, among germinal center tumors, “there was not a hint of any difference,” Dr Zelenetz noted.

Two studies—E1412, using an unselected population, and the international ROBUST study, selecting for patients with ABC tumors—are underway to confirm that the benefit with lenalidomide is in patients with activated B-cell tumors.

Ibrutinib

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, also has modest activity as a single agent in an unselected patient population with relapsed/refractory DLBCL. And most of the patients who demonstrated benefit had activated B-cell tumors.

Upon further analysis, investigators found that response was enhanced by the CD79b mutation, but it was not necessary for a response. And patients with CARD11 had no response.

MYD88 mutations seemed to cause resistance to ibrutinib, unless the mutation was associated with the CD79b mutation, and then patients had a “great” response, Dr Zelenetz explained.

In the upfront setting, a phase 1b study of R-CHOP plus ibrutinib demonstrated the safety of the combination, which had an overall survival rate of 100% and a complete response rate of 91%.

The prospective, randomized, phase 3 PHOENIX trial (NCT01855750) evaluating the combination in newly diagnosed non-germinal center DLBCL has completed accrual, but analysis is still pending.

Conclusion

“The prognostic significance of cell of origin is still controversial,” Dr Zelenetz wrapped up, “although I actually believe there is a prognostic difference in unselected registry patients.”

Sequential chemotherapy with ifosfamide and etoposide consolidation does very well in activated B-cell tumors, both in phase 2 and phase 3 studies.

“Importantly, small molecules seem to have differential effects totally predictable based on the biology of the difference between activated B-cell and germinal center tumors,” Dr Zelenetz said.

“But the big wild card here is somatic mutations further complicate things and will have to be incorporated into our understanding in the selection of patients.”

Andrew Zelenetz, MD, PhD

NEW YORK—The importance of cell of origin in choosing a treatment for diffuse large B-cell lymphoma (DLBCL) is a topic “that has been kicking around for 16 years,” according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.

Cell of origin was first described in the year 2000 as a distinguishing factor in large-cell lymphoma, said the speaker, Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York.

The cell of origin in DLBCL—whether it’s germinal center B cell (GCB), activated B cell (ABC), or unclassified—contributes to biological and clinical heterogeneity of the disease.

“And more importantly, activated B-cell diffuse large B-cell lymphoma and germinal center diffuse large B-cell lymphoma are simply different diseases,” Dr Zelenetz said.

He then elaborated on the importance of cell of origin in treating DLBCL.

Biology

Dr Zelenetz noted that ABC and GCB lymphomas have different molecular pathways. ABC lymphomas are very dependent on the NF-kB pathway and have more active signaling through the B-cell receptor.

The GCB lymphomas tend to have more tonic regulation, and the PI3 kinase/mTOR pathway is more critical. GCB lymphomas have more genomic instability.

“So cell of origin determination identifies tumors with distinct biology, may provide prognostic information, and may be predictive for treatment selection,” Dr Zelenetz said. “Unfortunately, cell of origin is not the whole story.” 

Gene mutations occur in large-cell lymphoma “just like every other cancer,” Dr Zelenetz said. And the vast majority occur in both lymphoma subtypes, he added, further complicating our understanding of the biology of these tumors.

Some of these mutations predict for sensitivity to treatment, while others predict for resistance. For example, CARD11 predicts for resistance to ibrutinib, while CD79b predicts for sensitivity.

Determining the cell of origin

Gene-expression profiling on fresh tissue is considered the gold standard, but “it is clearly not a clinical tool,” Dr Zelenetz said.  It requires the Wright classifier, a statistical method based on Bayes’ rule, to make patient-level assignments to 1 of the 3 subgroups.

Immunohistochemistry is widely available, but reproducibility may be difficult. Many assays exist, such as the Hans, Choi, and Muris assays, but, in many studies, there may be a lack of correlation with gene-expression profiling.

In the last few years, gene-expression profiling of formalin‐fixed paraffin‐embedded (FFPE) tissue has emerged as a reliable method. The assay is reproducible between laboratories, and it’s reproducible between different sets of reagents.

“[T]here is tremendous correlation between the Lymph2Cx assay and the gold standard,” Dr Zelenetz added.

“So here we have a robust assay,” he said, which allows investigators to explore whether the cell of origin is prognostic in large-cell lymphoma.

Prognosis

In a data set of 339 patients with de novo DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), the Lymph2Cx assay showing cell of origin was predictive of overall and progression-free survival.

However, the same exact assay applied to the RICOVER-60 data from the German High-Grade Non-Hodgkin Lymphoma Study group was not predictive, Dr Zelenetz reported, based on a personal communication from one of the investigators. There was a slight trend in favor of GCB tumors, but it was not statistically significant.

And the REMoDL-B study, using gene-expression profiling of FFPE tissue with the DASL assay, also didn’t show any difference in outcome between ABC or GCB tumors.

So gene-expression profiling of FFPE tissue does not universally show a prognostic difference, Dr Zelenetz said.

Influence of chemotherapy by cell of origin

CALGB 59910 showed that GCB tumors had a superior event-free, progression-free, and overall survival with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) compared to ABC tumors.

“However, this is a phase 2, hypothesis-generating experiment,” Dr Zelenetz pointed out, and the results of the confirmatory study comparing dose-adjusted EPOCH-R and R-CHOP21 (CALGB 50303) will be presented later this year at the ASH Annual Meeting.

Sequential, non-cross-resistant chemotherapy

Data from the Memorial Sloan Kettering study (MSKCC 01-142/08-146; NCT00712582) of sequential therapy with R-CHOP followed by ICE (ifosfamide, carboplatin, and etoposide) demonstrate “excellent” progression-free and overall survival, Dr Zelenetz said.

“When we analyzed the outcome by cell of origin, there was a suggestion that the patients with the non-germinal center tumors were actually doing better than the germinal center tumors,” he added.

He pointed out one of the limitations of the study is that the cell of origin was determined by the Hans model. Nevertheless, the study raised another testable hypothesis: sequential therapy might overcome the adverse impact of the non-germinal center tumors.

Cell of origin analysis of the prospective, randomized study (LNH 03-2B) comparing R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) to R-CHOP showed that whether patients with GCB tumors received CHOP or ACVBP didn’t make “a whit of difference,” Dr Zelenetz said, in terms of progression-free and overall survival.

However, patients with ABC tumors demonstrated an “enormous difference in favor of R-ACVBP,” he said.

“Again, evidence that you can overcome the adverse effect of the ABC tumors with chemotherapy.”

Dr Zelenetz pointed out that R-ACVBP and R-CHOP followed by ICE are “actually remarkably similar regimens.” Both are sequential, both include consolidation, and both incorporate high-dose ifosfamide and etoposide.

“[S]o they actually reinforce each other,” he said, “demonstrating a similar result.”

Lenalidomide

Lenalidomide in the relapsed/refractory setting has modest activity in DLBCL, with most of the benefit accruing to patients with non-germinal center tumors.

Two clinical studies evaluated the impact of adding lenalidomide to standard chemotherapy.

In an Italian series using lenalidomide (L) plus R-CHOP21 in elderly untreated patients, the combination produced outstanding progression-free and event-free survival, but with no significant differences between the subtypes.

A US study of RL-CHOP versus R-CHOP included 87 matched historical controls treated with R-CHOP and 64 patients treated with RL-CHOP. Patients with non-germinal center tumors treated with RL-CHOP fared much better than historical controls treated with R-CHOP.

However, among germinal center tumors, “there was not a hint of any difference,” Dr Zelenetz noted.

Two studies—E1412, using an unselected population, and the international ROBUST study, selecting for patients with ABC tumors—are underway to confirm that the benefit with lenalidomide is in patients with activated B-cell tumors.

Ibrutinib

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, also has modest activity as a single agent in an unselected patient population with relapsed/refractory DLBCL. And most of the patients who demonstrated benefit had activated B-cell tumors.

Upon further analysis, investigators found that response was enhanced by the CD79b mutation, but it was not necessary for a response. And patients with CARD11 had no response.

MYD88 mutations seemed to cause resistance to ibrutinib, unless the mutation was associated with the CD79b mutation, and then patients had a “great” response, Dr Zelenetz explained.

In the upfront setting, a phase 1b study of R-CHOP plus ibrutinib demonstrated the safety of the combination, which had an overall survival rate of 100% and a complete response rate of 91%.

The prospective, randomized, phase 3 PHOENIX trial (NCT01855750) evaluating the combination in newly diagnosed non-germinal center DLBCL has completed accrual, but analysis is still pending.

Conclusion

“The prognostic significance of cell of origin is still controversial,” Dr Zelenetz wrapped up, “although I actually believe there is a prognostic difference in unselected registry patients.”

Sequential chemotherapy with ifosfamide and etoposide consolidation does very well in activated B-cell tumors, both in phase 2 and phase 3 studies.

“Importantly, small molecules seem to have differential effects totally predictable based on the biology of the difference between activated B-cell and germinal center tumors,” Dr Zelenetz said.

“But the big wild card here is somatic mutations further complicate things and will have to be incorporated into our understanding in the selection of patients.”

First month’s supply

of venetoclax (Venclexta)

Photo courtesy of AbbVie

Health Canada has issued a Notice of Compliance with Conditions (NOC/c) for the BCL-2 inhibitor venetoclax (Venclexta™).

This means venetoclax is conditionally approved for use in patients with previously treated chronic lymphocytic leukemia (CLL) who have 17p deletion or no other available treatment options.

An NOC/c is authorization to market a drug with the condition that the sponsor perform additional studies to verify a clinical benefit.

The NOC/c policy is designed to provide access to:

• Drugs that can treat serious, life-threatening, or severely debilitating diseases
• Drugs that can treat conditions for which no drug is currently marketed in Canada
• Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.

Venetoclax (previously ABT‐199) is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Venetoclax is currently under evaluation in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Phase 2 trial

Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.

Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.

At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.

Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.

At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

The incidence of serious adverse events was 55%. The most common of these events were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

First month’s supply

of venetoclax (Venclexta)

Photo courtesy of AbbVie

Health Canada has issued a Notice of Compliance with Conditions (NOC/c) for the BCL-2 inhibitor venetoclax (Venclexta™).

This means venetoclax is conditionally approved for use in patients with previously treated chronic lymphocytic leukemia (CLL) who have 17p deletion or no other available treatment options.

An NOC/c is authorization to market a drug with the condition that the sponsor perform additional studies to verify a clinical benefit.

The NOC/c policy is designed to provide access to:

• Drugs that can treat serious, life-threatening, or severely debilitating diseases
• Drugs that can treat conditions for which no drug is currently marketed in Canada
• Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.

Venetoclax (previously ABT‐199) is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Venetoclax is currently under evaluation in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Phase 2 trial

Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.

Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.

At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.

Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.

At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

The incidence of serious adverse events was 55%. The most common of these events were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

First month’s supply

of venetoclax (Venclexta)

Photo courtesy of AbbVie

Health Canada has issued a Notice of Compliance with Conditions (NOC/c) for the BCL-2 inhibitor venetoclax (Venclexta™).

This means venetoclax is conditionally approved for use in patients with previously treated chronic lymphocytic leukemia (CLL) who have 17p deletion or no other available treatment options.

An NOC/c is authorization to market a drug with the condition that the sponsor perform additional studies to verify a clinical benefit.

The NOC/c policy is designed to provide access to:

• Drugs that can treat serious, life-threatening, or severely debilitating diseases
• Drugs that can treat conditions for which no drug is currently marketed in Canada
• Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.

Venetoclax (previously ABT‐199) is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Venetoclax is currently under evaluation in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Phase 2 trial

Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.

Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.

At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.

Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.

At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

The incidence of serious adverse events was 55%. The most common of these events were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

Chromosomes in red with

telomeres in green

Image by Claus Azzalin

New research indicates that an enzyme called uracil-DNA glycosylase (UNG) protects the ends of B-cell chromosomes to facilitate B-cell proliferation in response to infection.

The study also suggests that targeting UNG may help treat certain types of non-Hodgkin lymphoma (NHL).

Ramiro Verdun, PhD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described the study in The Journal of Experimental Medicine.

The researchers knew that when a B cell first encounters a foreign antigen, it starts to proliferate and produce a DNA-modifying enzyme called activation-induced deaminase (AID).

AID creates mutations in the cell’s immunoglobulin genes so the cell’s progeny produce a diverse array of antibodies that can bind the antigen with high affinity and mediate various immune responses.

But AID can create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by UNG or other DNA repair proteins, this can lead to NHL and other cancers.

Dr Verdun and his colleagues decided to investigate whether AID targets the telomeres of mouse B cells. They chose this path of investigation because telomeres contain similar DNA sequences to immunoglobulin genes.

The researchers found that, in the absence of UNG, AID created mutations in B-cell telomeres that caused them to rapidly shorten, limiting the proliferation of activated B cells.

UNG helped to repair these mutations, preventing telomere loss and facilitating B-cell expansion. UNG enabled the B cells to continue proliferating while they mutated their immunoglobulin genes, allowing them to mount an effective immune response.

Finally, the researchers found that UNG’s activity may also help NHL cells, which often overexpress AID, to continue proliferating.

The team tested human diffuse large B-cell lymphoma (DLBCL) cells with high or low expression of AID. And they found that inhibiting UNG impaired the growth of DLBCL cells with high AID expression but had no effect on DLBCL cells with low AID expression.

“We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers,” Dr Verdun said.

Chromosomes in red with

telomeres in green

Image by Claus Azzalin

New research indicates that an enzyme called uracil-DNA glycosylase (UNG) protects the ends of B-cell chromosomes to facilitate B-cell proliferation in response to infection.

The study also suggests that targeting UNG may help treat certain types of non-Hodgkin lymphoma (NHL).

Ramiro Verdun, PhD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described the study in The Journal of Experimental Medicine.

The researchers knew that when a B cell first encounters a foreign antigen, it starts to proliferate and produce a DNA-modifying enzyme called activation-induced deaminase (AID).

AID creates mutations in the cell’s immunoglobulin genes so the cell’s progeny produce a diverse array of antibodies that can bind the antigen with high affinity and mediate various immune responses.

But AID can create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by UNG or other DNA repair proteins, this can lead to NHL and other cancers.

Dr Verdun and his colleagues decided to investigate whether AID targets the telomeres of mouse B cells. They chose this path of investigation because telomeres contain similar DNA sequences to immunoglobulin genes.

The researchers found that, in the absence of UNG, AID created mutations in B-cell telomeres that caused them to rapidly shorten, limiting the proliferation of activated B cells.

UNG helped to repair these mutations, preventing telomere loss and facilitating B-cell expansion. UNG enabled the B cells to continue proliferating while they mutated their immunoglobulin genes, allowing them to mount an effective immune response.

Finally, the researchers found that UNG’s activity may also help NHL cells, which often overexpress AID, to continue proliferating.

The team tested human diffuse large B-cell lymphoma (DLBCL) cells with high or low expression of AID. And they found that inhibiting UNG impaired the growth of DLBCL cells with high AID expression but had no effect on DLBCL cells with low AID expression.

“We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers,” Dr Verdun said.

Chromosomes in red with

telomeres in green

Image by Claus Azzalin

New research indicates that an enzyme called uracil-DNA glycosylase (UNG) protects the ends of B-cell chromosomes to facilitate B-cell proliferation in response to infection.

The study also suggests that targeting UNG may help treat certain types of non-Hodgkin lymphoma (NHL).

Ramiro Verdun, PhD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described the study in The Journal of Experimental Medicine.

The researchers knew that when a B cell first encounters a foreign antigen, it starts to proliferate and produce a DNA-modifying enzyme called activation-induced deaminase (AID).

AID creates mutations in the cell’s immunoglobulin genes so the cell’s progeny produce a diverse array of antibodies that can bind the antigen with high affinity and mediate various immune responses.

But AID can create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by UNG or other DNA repair proteins, this can lead to NHL and other cancers.

Dr Verdun and his colleagues decided to investigate whether AID targets the telomeres of mouse B cells. They chose this path of investigation because telomeres contain similar DNA sequences to immunoglobulin genes.

The researchers found that, in the absence of UNG, AID created mutations in B-cell telomeres that caused them to rapidly shorten, limiting the proliferation of activated B cells.

UNG helped to repair these mutations, preventing telomere loss and facilitating B-cell expansion. UNG enabled the B cells to continue proliferating while they mutated their immunoglobulin genes, allowing them to mount an effective immune response.

Finally, the researchers found that UNG’s activity may also help NHL cells, which often overexpress AID, to continue proliferating.

The team tested human diffuse large B-cell lymphoma (DLBCL) cells with high or low expression of AID. And they found that inhibiting UNG impaired the growth of DLBCL cells with high AID expression but had no effect on DLBCL cells with low AID expression.

“We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers,” Dr Verdun said.