Lymphoma & Plasma Cell Disorders

 

NEW YORK—Two presentations at the NCCN 11th Annual Congress: Hematologic Malignancies addressed the importance of supportive care in the treatment of patients with T-cell lymphomas and multiple myeloma.

Erin Kopp, ACNP-BC, of City of Hope Comprehensive Cancer Center in Duarte, California, reminded the audience that supportive care is not palliative care.

Supportive care “complements critical care so that the patient doesn’t have to stop treatment,” she said.

Kopp focused primarily on cutaneous T-cell lymphoma (CTCL) in her presentation, with some recommendations for managing tumor lysis syndrome in patients undergoing therapy for peripheral T-cell lymphoma (PTCL).

And Kathleen Colson, RN, of the Dana-Farber Cancer Institute in Boston, Massachusetts, discussed supportive care for patients with multiple myeloma (MM).

T-cell lymphomas

Most T-cell lymphoma patients will require multiple treatment regimens over their lifetimes, Kopp said. And each type of therapy brings different treatment-related toxicities, which in turn require distinct supportive care measures to manage them.

Topical steroids, for example, may cause skin-thinning, stretch marks, skin irritation, and may be absorbed systemically when a high-potency formulation is used. So the lowest potency steroid that provides the maximum efficacy should be utilized. Practitioners should assess systemic effects if high-potency steroids are utilized.

Topical nitrogen mustard can darken the skin, which often occurs as the lesions resolve, Kopp said. She cautioned that patients experiencing hyperpigmentation often stop treatment without telling their physicians. 

So Kopp recommends appropriate patient education to go along with the treatment. With nitrogen mustard, this includes applying a thin layer only to the affected areas and refrigerating the topical ointment to increase soothing. 

Topical retinoids may cause redness, itching, warmth, swelling, burning, scaling or other irritation. They also increase the patients’ sensitivity to light. Kopp indicated that for the first week, topical retinoids should be applied once every other day and then titrated as tolerated.

Phototherapy with PUVA or narrowband-UVB may also cause itching, in addition to skin burn, nausea, and other side effects.

“Do not underestimate emollients,” Kopp said, for relief of pruritus. And skin baths with bleach significantly decrease infections that may result from treatment.

Systemic therapy with retinoids, interferon, cytotoxic agents, monoclonal antibodies, and HDAC inhibitors may also cause distinct reactions. For example, the retinoid bexarotene may cause primary hypothyroidism and major lipid abnormalities. Therefore, TSH, free T4, and triglycerides should be monitored every 8 weeks.

Cytotoxic agents such as pralatrexate and methotrexate significantly increase the risk for infection.

Monoclonal antibodies can reactivate previous viral infection, induce tumor lysis syndrome (TLS), and cause progressive multifocal leukoencephalopathy.

HDAC inhibitors such as vorinostat and romidepsin may cause QT prolongation and myelosuppression, among other side effects.

Practitioners need to assess symptoms and side effects thoroughly and often and provide options for supportive care management.

PTCL is an under recognized risk for TLS, Kopp said.

“It should be addressed aggressively,” she added, with monitoring and correction of electrolyte imbalance.

Patients should be rigorously hydrated, and allopurinol should be administered 2-3 days prior to treatment and adjusted based on the patient response and uric acid level.

Multiple myeloma

Colson described supportive care as “keeping all the pieces together.” MM itself can result in a broad spectrum of clinical manifestations, including renal compromise, neuropathy, infection, hypercalcemia, bone pain, lytic lesions, and anemia. 

To preserve renal health, patients should drink plenty of water and avoid certain medications, such as IV contrast and nonsteroidal anti-inflammatory drugs. 

Peripheral neuropathy can be a side effect of treatment or be caused by the disease itself. Bortezomib-related neuropathy can be reduced with weekly instead of twice weekly dosing and with subcutaneous administration.

Duration of higher doses of thalidomide treatment also impacts neuropathy. Carfilzomib and pomalidomide have a lower incidence of neuropathy. 

 

Myeloma patients have a 15-fold increased risk of recurrent infection because white blood cell production is decreased and the normal immune role of plasma cells is lost.

Supportive therapy includes antibiotics and IVIG therapy. In addition, Colson said pneumonia and influenza vaccines should be considered, as well as prophylaxis for Pneumocystis carinii, herpes zoster, and fungal infections.

Hypercalcemia results from increased bone deterioration. Symptoms include loss of appetite, fatigue, vomiting, muscle weakness, confusion, constipation, increased thirst, and increased urine output. Supportive measures are adequate hydration, furosemide, bisphosphonates, and steroids.

Supportive therapy for bone pain includes bisphosphonates, radiation, pain medication, kyphoplasty, and vertebroplasty. Bisphosphonates, such as pamidronate and zoledronic acid, inhibit bone destruction and are recommended for all myeloma patients with bone disease. However, patients should be monitored for renal dysfunction and osteonecrosis of the jaw when taking bisphosphonates.

And Colson advises, “Hold bisphosphonate therapy if the patient needs a root canal or extraction.” Additionally, dental implants are not recommended for MM patients.

Anemia is another common presenting symptom of myeloma and may also be a result of decreased kidney function. Colson said the use of red blood cell supplements may be used with caution to ameliorate the symptom. Red blood cell transfusion may be considered and a reduction in the medication dose may be required.

MM is a hypercoagulable disease, and measures should be taken to avoid deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients should wear anti-embolism stockings, exercise regularly, take low-dose aspirin, and move about frequently instead of sitting for long periods. Immunomodulatory medications may be adjusted to reduce the risk of a blot clot forming.

Infusion-related reactions are also a risk of therapy, and symptoms of a reaction need to be managed immediately and appropriately, with antihistamines, corticosteroids, interruption of the infusion, slowing of the infusion rate after symptom resolution, and permanent discontinuation in the case of grade 4 reactions.

The potential for longer survival exists, Colson said, due to appropriate supportive care measures.

 

NEW YORK—Two presentations at the NCCN 11th Annual Congress: Hematologic Malignancies addressed the importance of supportive care in the treatment of patients with T-cell lymphomas and multiple myeloma.

Erin Kopp, ACNP-BC, of City of Hope Comprehensive Cancer Center in Duarte, California, reminded the audience that supportive care is not palliative care.

Supportive care “complements critical care so that the patient doesn’t have to stop treatment,” she said.

Kopp focused primarily on cutaneous T-cell lymphoma (CTCL) in her presentation, with some recommendations for managing tumor lysis syndrome in patients undergoing therapy for peripheral T-cell lymphoma (PTCL).

And Kathleen Colson, RN, of the Dana-Farber Cancer Institute in Boston, Massachusetts, discussed supportive care for patients with multiple myeloma (MM).

T-cell lymphomas

Most T-cell lymphoma patients will require multiple treatment regimens over their lifetimes, Kopp said. And each type of therapy brings different treatment-related toxicities, which in turn require distinct supportive care measures to manage them.

Topical steroids, for example, may cause skin-thinning, stretch marks, skin irritation, and may be absorbed systemically when a high-potency formulation is used. So the lowest potency steroid that provides the maximum efficacy should be utilized. Practitioners should assess systemic effects if high-potency steroids are utilized.

Topical nitrogen mustard can darken the skin, which often occurs as the lesions resolve, Kopp said. She cautioned that patients experiencing hyperpigmentation often stop treatment without telling their physicians. 

So Kopp recommends appropriate patient education to go along with the treatment. With nitrogen mustard, this includes applying a thin layer only to the affected areas and refrigerating the topical ointment to increase soothing. 

Topical retinoids may cause redness, itching, warmth, swelling, burning, scaling or other irritation. They also increase the patients’ sensitivity to light. Kopp indicated that for the first week, topical retinoids should be applied once every other day and then titrated as tolerated.

Phototherapy with PUVA or narrowband-UVB may also cause itching, in addition to skin burn, nausea, and other side effects.

“Do not underestimate emollients,” Kopp said, for relief of pruritus. And skin baths with bleach significantly decrease infections that may result from treatment.

Systemic therapy with retinoids, interferon, cytotoxic agents, monoclonal antibodies, and HDAC inhibitors may also cause distinct reactions. For example, the retinoid bexarotene may cause primary hypothyroidism and major lipid abnormalities. Therefore, TSH, free T4, and triglycerides should be monitored every 8 weeks.

Cytotoxic agents such as pralatrexate and methotrexate significantly increase the risk for infection.

Monoclonal antibodies can reactivate previous viral infection, induce tumor lysis syndrome (TLS), and cause progressive multifocal leukoencephalopathy.

HDAC inhibitors such as vorinostat and romidepsin may cause QT prolongation and myelosuppression, among other side effects.

Practitioners need to assess symptoms and side effects thoroughly and often and provide options for supportive care management.

PTCL is an under recognized risk for TLS, Kopp said.

“It should be addressed aggressively,” she added, with monitoring and correction of electrolyte imbalance.

Patients should be rigorously hydrated, and allopurinol should be administered 2-3 days prior to treatment and adjusted based on the patient response and uric acid level.

Multiple myeloma

Colson described supportive care as “keeping all the pieces together.” MM itself can result in a broad spectrum of clinical manifestations, including renal compromise, neuropathy, infection, hypercalcemia, bone pain, lytic lesions, and anemia. 

To preserve renal health, patients should drink plenty of water and avoid certain medications, such as IV contrast and nonsteroidal anti-inflammatory drugs. 

Peripheral neuropathy can be a side effect of treatment or be caused by the disease itself. Bortezomib-related neuropathy can be reduced with weekly instead of twice weekly dosing and with subcutaneous administration.

Duration of higher doses of thalidomide treatment also impacts neuropathy. Carfilzomib and pomalidomide have a lower incidence of neuropathy. 

 

Myeloma patients have a 15-fold increased risk of recurrent infection because white blood cell production is decreased and the normal immune role of plasma cells is lost.

Supportive therapy includes antibiotics and IVIG therapy. In addition, Colson said pneumonia and influenza vaccines should be considered, as well as prophylaxis for Pneumocystis carinii, herpes zoster, and fungal infections.

Hypercalcemia results from increased bone deterioration. Symptoms include loss of appetite, fatigue, vomiting, muscle weakness, confusion, constipation, increased thirst, and increased urine output. Supportive measures are adequate hydration, furosemide, bisphosphonates, and steroids.

Supportive therapy for bone pain includes bisphosphonates, radiation, pain medication, kyphoplasty, and vertebroplasty. Bisphosphonates, such as pamidronate and zoledronic acid, inhibit bone destruction and are recommended for all myeloma patients with bone disease. However, patients should be monitored for renal dysfunction and osteonecrosis of the jaw when taking bisphosphonates.

And Colson advises, “Hold bisphosphonate therapy if the patient needs a root canal or extraction.” Additionally, dental implants are not recommended for MM patients.

Anemia is another common presenting symptom of myeloma and may also be a result of decreased kidney function. Colson said the use of red blood cell supplements may be used with caution to ameliorate the symptom. Red blood cell transfusion may be considered and a reduction in the medication dose may be required.

MM is a hypercoagulable disease, and measures should be taken to avoid deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients should wear anti-embolism stockings, exercise regularly, take low-dose aspirin, and move about frequently instead of sitting for long periods. Immunomodulatory medications may be adjusted to reduce the risk of a blot clot forming.

Infusion-related reactions are also a risk of therapy, and symptoms of a reaction need to be managed immediately and appropriately, with antihistamines, corticosteroids, interruption of the infusion, slowing of the infusion rate after symptom resolution, and permanent discontinuation in the case of grade 4 reactions.

The potential for longer survival exists, Colson said, due to appropriate supportive care measures.

 

NEW YORK—Two presentations at the NCCN 11th Annual Congress: Hematologic Malignancies addressed the importance of supportive care in the treatment of patients with T-cell lymphomas and multiple myeloma.

Erin Kopp, ACNP-BC, of City of Hope Comprehensive Cancer Center in Duarte, California, reminded the audience that supportive care is not palliative care.

Supportive care “complements critical care so that the patient doesn’t have to stop treatment,” she said.

Kopp focused primarily on cutaneous T-cell lymphoma (CTCL) in her presentation, with some recommendations for managing tumor lysis syndrome in patients undergoing therapy for peripheral T-cell lymphoma (PTCL).

And Kathleen Colson, RN, of the Dana-Farber Cancer Institute in Boston, Massachusetts, discussed supportive care for patients with multiple myeloma (MM).

T-cell lymphomas

Most T-cell lymphoma patients will require multiple treatment regimens over their lifetimes, Kopp said. And each type of therapy brings different treatment-related toxicities, which in turn require distinct supportive care measures to manage them.

Topical steroids, for example, may cause skin-thinning, stretch marks, skin irritation, and may be absorbed systemically when a high-potency formulation is used. So the lowest potency steroid that provides the maximum efficacy should be utilized. Practitioners should assess systemic effects if high-potency steroids are utilized.

Topical nitrogen mustard can darken the skin, which often occurs as the lesions resolve, Kopp said. She cautioned that patients experiencing hyperpigmentation often stop treatment without telling their physicians. 

So Kopp recommends appropriate patient education to go along with the treatment. With nitrogen mustard, this includes applying a thin layer only to the affected areas and refrigerating the topical ointment to increase soothing. 

Topical retinoids may cause redness, itching, warmth, swelling, burning, scaling or other irritation. They also increase the patients’ sensitivity to light. Kopp indicated that for the first week, topical retinoids should be applied once every other day and then titrated as tolerated.

Phototherapy with PUVA or narrowband-UVB may also cause itching, in addition to skin burn, nausea, and other side effects.

“Do not underestimate emollients,” Kopp said, for relief of pruritus. And skin baths with bleach significantly decrease infections that may result from treatment.

Systemic therapy with retinoids, interferon, cytotoxic agents, monoclonal antibodies, and HDAC inhibitors may also cause distinct reactions. For example, the retinoid bexarotene may cause primary hypothyroidism and major lipid abnormalities. Therefore, TSH, free T4, and triglycerides should be monitored every 8 weeks.

Cytotoxic agents such as pralatrexate and methotrexate significantly increase the risk for infection.

Monoclonal antibodies can reactivate previous viral infection, induce tumor lysis syndrome (TLS), and cause progressive multifocal leukoencephalopathy.

HDAC inhibitors such as vorinostat and romidepsin may cause QT prolongation and myelosuppression, among other side effects.

Practitioners need to assess symptoms and side effects thoroughly and often and provide options for supportive care management.

PTCL is an under recognized risk for TLS, Kopp said.

“It should be addressed aggressively,” she added, with monitoring and correction of electrolyte imbalance.

Patients should be rigorously hydrated, and allopurinol should be administered 2-3 days prior to treatment and adjusted based on the patient response and uric acid level.

Multiple myeloma

Colson described supportive care as “keeping all the pieces together.” MM itself can result in a broad spectrum of clinical manifestations, including renal compromise, neuropathy, infection, hypercalcemia, bone pain, lytic lesions, and anemia. 

To preserve renal health, patients should drink plenty of water and avoid certain medications, such as IV contrast and nonsteroidal anti-inflammatory drugs. 

Peripheral neuropathy can be a side effect of treatment or be caused by the disease itself. Bortezomib-related neuropathy can be reduced with weekly instead of twice weekly dosing and with subcutaneous administration.

Duration of higher doses of thalidomide treatment also impacts neuropathy. Carfilzomib and pomalidomide have a lower incidence of neuropathy. 

 

Myeloma patients have a 15-fold increased risk of recurrent infection because white blood cell production is decreased and the normal immune role of plasma cells is lost.

Supportive therapy includes antibiotics and IVIG therapy. In addition, Colson said pneumonia and influenza vaccines should be considered, as well as prophylaxis for Pneumocystis carinii, herpes zoster, and fungal infections.

Hypercalcemia results from increased bone deterioration. Symptoms include loss of appetite, fatigue, vomiting, muscle weakness, confusion, constipation, increased thirst, and increased urine output. Supportive measures are adequate hydration, furosemide, bisphosphonates, and steroids.

Supportive therapy for bone pain includes bisphosphonates, radiation, pain medication, kyphoplasty, and vertebroplasty. Bisphosphonates, such as pamidronate and zoledronic acid, inhibit bone destruction and are recommended for all myeloma patients with bone disease. However, patients should be monitored for renal dysfunction and osteonecrosis of the jaw when taking bisphosphonates.

And Colson advises, “Hold bisphosphonate therapy if the patient needs a root canal or extraction.” Additionally, dental implants are not recommended for MM patients.

Anemia is another common presenting symptom of myeloma and may also be a result of decreased kidney function. Colson said the use of red blood cell supplements may be used with caution to ameliorate the symptom. Red blood cell transfusion may be considered and a reduction in the medication dose may be required.

MM is a hypercoagulable disease, and measures should be taken to avoid deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients should wear anti-embolism stockings, exercise regularly, take low-dose aspirin, and move about frequently instead of sitting for long periods. Immunomodulatory medications may be adjusted to reduce the risk of a blot clot forming.

Infusion-related reactions are also a risk of therapy, and symptoms of a reaction need to be managed immediately and appropriately, with antihistamines, corticosteroids, interruption of the infusion, slowing of the infusion rate after symptom resolution, and permanent discontinuation in the case of grade 4 reactions.

The potential for longer survival exists, Colson said, due to appropriate supportive care measures.

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.”

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.”

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.”

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.

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.

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.

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.

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.

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.

The Lymphoma Association has launched Lymphoma TrialsLink, an online information service that can help lymphoma patients in the UK find clinical trials that might be right for them.

Lymphoma TrialsLink pulls information from different clinical trials databases and puts it in one place.

Lymphoma TrialsLink also provides information about different types of clinical trials and interviews with clinicians and patients who have participated in trials.

The service is available via the Lymphoma Association website: www.lymphomas.org.uk/TrialsLink.

At Lymphoma TrialsLink, patients can search by their type of lymphoma and geographical location to find easy-to-understand information about trials.

At present, treatment trials (phases 1/2 and 2/3), non-drug and non-treatment trials, and cross-tumoral trials that are currently recruiting participants in the UK are available on the Lymphoma TrialsLink website. Information on phase 1, phase 4, and invitation-only trials will be introduced in 2017.

Trial information, which is searchable by type of lymphoma and location, is sourced from a number of databases, including Cancer Research UK trials, UK clinical trials gateway, clinicaltrials.gov, and the NCRI Lymphoma Clinical Studies Group.

The data is verified by the coordinating trial center to ensure that closing dates and trial centers are up-to-date. The content on Lymphoma TrialsLink will be updated monthly.

“Clinical trials are essential for investigating drugs for the treatment of lymphatic cancer and improving survivorship rates,” said Jonathan Pearce, Lymphoma Association chief executive.

“Clinical trials aren’t right for everyone, but we want people to feel empowered to make an informed decision. Lymphoma TrialsLink will mean that lymphoma patients who aren’t currently aware of clinical trials will have the opportunity to find out more about relevant trials and make the best possible decisions about their healthcare.”

A recent Lymphoma Association survey of more than 3000 lymphoma patients* revealed that 78% were not given the option of participating in a clinical trial. Of those who were, the majority joined a trial.

“Lymphoma is the UK’s fifth most common cancer, yet it is neither well-known nor easily understood,” Pearce noted. “We are committed to supporting clinical research to help improve knowledge of lymphoma, to drive advances in treatments, and to deliver better outcomes for people affected by lymphoma.”

Lymphoma TrialsLink is funded by voluntary donations from Lymphoma Association supporters who responded to a fundraising appeal earlier this year.

*A quality health survey commissioned in 2016 by the Lymphoma Association. The full results of the survey are expected to be published soon.

The Lymphoma Association has launched Lymphoma TrialsLink, an online information service that can help lymphoma patients in the UK find clinical trials that might be right for them.

Lymphoma TrialsLink pulls information from different clinical trials databases and puts it in one place.

Lymphoma TrialsLink also provides information about different types of clinical trials and interviews with clinicians and patients who have participated in trials.

The service is available via the Lymphoma Association website: www.lymphomas.org.uk/TrialsLink.

At Lymphoma TrialsLink, patients can search by their type of lymphoma and geographical location to find easy-to-understand information about trials.

At present, treatment trials (phases 1/2 and 2/3), non-drug and non-treatment trials, and cross-tumoral trials that are currently recruiting participants in the UK are available on the Lymphoma TrialsLink website. Information on phase 1, phase 4, and invitation-only trials will be introduced in 2017.

Trial information, which is searchable by type of lymphoma and location, is sourced from a number of databases, including Cancer Research UK trials, UK clinical trials gateway, clinicaltrials.gov, and the NCRI Lymphoma Clinical Studies Group.

The data is verified by the coordinating trial center to ensure that closing dates and trial centers are up-to-date. The content on Lymphoma TrialsLink will be updated monthly.

“Clinical trials are essential for investigating drugs for the treatment of lymphatic cancer and improving survivorship rates,” said Jonathan Pearce, Lymphoma Association chief executive.

“Clinical trials aren’t right for everyone, but we want people to feel empowered to make an informed decision. Lymphoma TrialsLink will mean that lymphoma patients who aren’t currently aware of clinical trials will have the opportunity to find out more about relevant trials and make the best possible decisions about their healthcare.”

A recent Lymphoma Association survey of more than 3000 lymphoma patients* revealed that 78% were not given the option of participating in a clinical trial. Of those who were, the majority joined a trial.

“Lymphoma is the UK’s fifth most common cancer, yet it is neither well-known nor easily understood,” Pearce noted. “We are committed to supporting clinical research to help improve knowledge of lymphoma, to drive advances in treatments, and to deliver better outcomes for people affected by lymphoma.”

Lymphoma TrialsLink is funded by voluntary donations from Lymphoma Association supporters who responded to a fundraising appeal earlier this year.

*A quality health survey commissioned in 2016 by the Lymphoma Association. The full results of the survey are expected to be published soon.

The Lymphoma Association has launched Lymphoma TrialsLink, an online information service that can help lymphoma patients in the UK find clinical trials that might be right for them.

Lymphoma TrialsLink pulls information from different clinical trials databases and puts it in one place.

Lymphoma TrialsLink also provides information about different types of clinical trials and interviews with clinicians and patients who have participated in trials.

The service is available via the Lymphoma Association website: www.lymphomas.org.uk/TrialsLink.

At Lymphoma TrialsLink, patients can search by their type of lymphoma and geographical location to find easy-to-understand information about trials.

At present, treatment trials (phases 1/2 and 2/3), non-drug and non-treatment trials, and cross-tumoral trials that are currently recruiting participants in the UK are available on the Lymphoma TrialsLink website. Information on phase 1, phase 4, and invitation-only trials will be introduced in 2017.

Trial information, which is searchable by type of lymphoma and location, is sourced from a number of databases, including Cancer Research UK trials, UK clinical trials gateway, clinicaltrials.gov, and the NCRI Lymphoma Clinical Studies Group.

The data is verified by the coordinating trial center to ensure that closing dates and trial centers are up-to-date. The content on Lymphoma TrialsLink will be updated monthly.

“Clinical trials are essential for investigating drugs for the treatment of lymphatic cancer and improving survivorship rates,” said Jonathan Pearce, Lymphoma Association chief executive.

“Clinical trials aren’t right for everyone, but we want people to feel empowered to make an informed decision. Lymphoma TrialsLink will mean that lymphoma patients who aren’t currently aware of clinical trials will have the opportunity to find out more about relevant trials and make the best possible decisions about their healthcare.”

A recent Lymphoma Association survey of more than 3000 lymphoma patients* revealed that 78% were not given the option of participating in a clinical trial. Of those who were, the majority joined a trial.

“Lymphoma is the UK’s fifth most common cancer, yet it is neither well-known nor easily understood,” Pearce noted. “We are committed to supporting clinical research to help improve knowledge of lymphoma, to drive advances in treatments, and to deliver better outcomes for people affected by lymphoma.”

Lymphoma TrialsLink is funded by voluntary donations from Lymphoma Association supporters who responded to a fundraising appeal earlier this year.

*A quality health survey commissioned in 2016 by the Lymphoma Association. The full results of the survey are expected to be published soon.

BOSTON—A new study suggests that roughly half of cancer patients in developing countries need radiation therapy (RT) to treat their disease, but many of these patients do not have access to it.

Examining 9 developing countries, investigators found that between 18% and 82% of patients who can benefit from RT do not receive the treatment.

These findings were presented at ASTRO’s 58th Annual Meeting (abstract 82).

“Access to radiation therapy remains limited in low-and middle-income countries,” said study investigator Elena Fidarova, MD, of the International Atomic Energy Agency in Vienna, Austria.

“In Ghana and the Philippines, for example, about 8 in 10 cancer patients who need radiation therapy will not receive needed treatment.”

Dr Fidarova and her colleagues conducted this study to assess levels of optimal and actual RT utilization (RTU) and calculate unmet RT need in 9 developing countries—Costa Rica, Ghana, Malaysia, the Philippines, Romania, Serbia, Slovenia, Tunisia, and Uruguay.

The investigators determined the optimal and actual RTU rates for each country. The optimal RTU rate is the proportion of all newly diagnosed cancer patients who have an indication for RT at least once in their lifetime.

An indication for RT was defined as a clinical scenario for which RT is recommended as the treatment of choice because there is evidence of its superiority to alternative modalities and/or no treatment (eg, better survival, local control, or quality of life profiles).

In clinical situations where RT was equivalent to other treatment options, all comparable modalities were included in the model, and a subsequent sensitivity analysis was conducted to determine the proportion of these patients for whom RT was indicated.

Results

The median optimal RTU for all countries was 52%. Optimal RTU rates ranged from a low of 47% for Costa Rica to a high of 56% for Tunisia. Differences in optimal RTU rates are attributable to varying incidence rates of cancer types in each country.

The median actual RTU rate was roughly half of optimal utilization, suggesting that nearly half of cancer patients across these 9 countries combined may not be receiving adequate care for their disease.

The median actual RTU rate was 28%. The lowest rates of utilization were in Ghana (9%) and the Philippines (10.3%), while the highest utilization rates were in Tunisia (46%) and Uruguay (37%).

Actual RTU rates were lower than optimal RTU rates for all 9 countries, with the smallest difference in Tunisia and the widest gap in Ghana—at nearly 43 percentage points.

The median level of unmet need was 47% for all countries combined.

Ghana and the Philippines had the highest levels of unmet need, at 82.3% and 80.5%, respectively. Costa Rica and Tunisia had the lowest levels of unmet need, at 25.5% and 18%, respectively.

The unmet need was especially high in countries with limited resources and a large population. The number of teletherapy machines per 1000 cancer cases ranged from a high of 1.3 in Tunisia to a low of 0.19 in Ghana.

The strong correlation between the actual RTU rates and the number of teletherapy machines per 1000 cancer cases/year in each country confirms that, although other access factors may be at play, the availability of RT machines is an important factor in RT utilization.

“Differences between optimal and actual RTU rates and the high percentage of unmet RT need likely stem from a number of complex reasons, although inadequate capacity for radiation therapy is the most obvious factor,” Dr Fidarova said.

“As obstacles in access to existing RT services—such as inadequate referral patterns, affordability of treatment, and geographical distribution of centers—differ by country, so does the ideal mix of solutions.”

BOSTON—A new study suggests that roughly half of cancer patients in developing countries need radiation therapy (RT) to treat their disease, but many of these patients do not have access to it.

Examining 9 developing countries, investigators found that between 18% and 82% of patients who can benefit from RT do not receive the treatment.

These findings were presented at ASTRO’s 58th Annual Meeting (abstract 82).

“Access to radiation therapy remains limited in low-and middle-income countries,” said study investigator Elena Fidarova, MD, of the International Atomic Energy Agency in Vienna, Austria.

“In Ghana and the Philippines, for example, about 8 in 10 cancer patients who need radiation therapy will not receive needed treatment.”

Dr Fidarova and her colleagues conducted this study to assess levels of optimal and actual RT utilization (RTU) and calculate unmet RT need in 9 developing countries—Costa Rica, Ghana, Malaysia, the Philippines, Romania, Serbia, Slovenia, Tunisia, and Uruguay.

The investigators determined the optimal and actual RTU rates for each country. The optimal RTU rate is the proportion of all newly diagnosed cancer patients who have an indication for RT at least once in their lifetime.

An indication for RT was defined as a clinical scenario for which RT is recommended as the treatment of choice because there is evidence of its superiority to alternative modalities and/or no treatment (eg, better survival, local control, or quality of life profiles).

In clinical situations where RT was equivalent to other treatment options, all comparable modalities were included in the model, and a subsequent sensitivity analysis was conducted to determine the proportion of these patients for whom RT was indicated.

Results

The median optimal RTU for all countries was 52%. Optimal RTU rates ranged from a low of 47% for Costa Rica to a high of 56% for Tunisia. Differences in optimal RTU rates are attributable to varying incidence rates of cancer types in each country.

The median actual RTU rate was roughly half of optimal utilization, suggesting that nearly half of cancer patients across these 9 countries combined may not be receiving adequate care for their disease.

The median actual RTU rate was 28%. The lowest rates of utilization were in Ghana (9%) and the Philippines (10.3%), while the highest utilization rates were in Tunisia (46%) and Uruguay (37%).

Actual RTU rates were lower than optimal RTU rates for all 9 countries, with the smallest difference in Tunisia and the widest gap in Ghana—at nearly 43 percentage points.

The median level of unmet need was 47% for all countries combined.

Ghana and the Philippines had the highest levels of unmet need, at 82.3% and 80.5%, respectively. Costa Rica and Tunisia had the lowest levels of unmet need, at 25.5% and 18%, respectively.

The unmet need was especially high in countries with limited resources and a large population. The number of teletherapy machines per 1000 cancer cases ranged from a high of 1.3 in Tunisia to a low of 0.19 in Ghana.

The strong correlation between the actual RTU rates and the number of teletherapy machines per 1000 cancer cases/year in each country confirms that, although other access factors may be at play, the availability of RT machines is an important factor in RT utilization.

“Differences between optimal and actual RTU rates and the high percentage of unmet RT need likely stem from a number of complex reasons, although inadequate capacity for radiation therapy is the most obvious factor,” Dr Fidarova said.

“As obstacles in access to existing RT services—such as inadequate referral patterns, affordability of treatment, and geographical distribution of centers—differ by country, so does the ideal mix of solutions.”

BOSTON—A new study suggests that roughly half of cancer patients in developing countries need radiation therapy (RT) to treat their disease, but many of these patients do not have access to it.

Examining 9 developing countries, investigators found that between 18% and 82% of patients who can benefit from RT do not receive the treatment.

These findings were presented at ASTRO’s 58th Annual Meeting (abstract 82).

“Access to radiation therapy remains limited in low-and middle-income countries,” said study investigator Elena Fidarova, MD, of the International Atomic Energy Agency in Vienna, Austria.

“In Ghana and the Philippines, for example, about 8 in 10 cancer patients who need radiation therapy will not receive needed treatment.”

Dr Fidarova and her colleagues conducted this study to assess levels of optimal and actual RT utilization (RTU) and calculate unmet RT need in 9 developing countries—Costa Rica, Ghana, Malaysia, the Philippines, Romania, Serbia, Slovenia, Tunisia, and Uruguay.

The investigators determined the optimal and actual RTU rates for each country. The optimal RTU rate is the proportion of all newly diagnosed cancer patients who have an indication for RT at least once in their lifetime.

An indication for RT was defined as a clinical scenario for which RT is recommended as the treatment of choice because there is evidence of its superiority to alternative modalities and/or no treatment (eg, better survival, local control, or quality of life profiles).

In clinical situations where RT was equivalent to other treatment options, all comparable modalities were included in the model, and a subsequent sensitivity analysis was conducted to determine the proportion of these patients for whom RT was indicated.

Results

The median optimal RTU for all countries was 52%. Optimal RTU rates ranged from a low of 47% for Costa Rica to a high of 56% for Tunisia. Differences in optimal RTU rates are attributable to varying incidence rates of cancer types in each country.

The median actual RTU rate was roughly half of optimal utilization, suggesting that nearly half of cancer patients across these 9 countries combined may not be receiving adequate care for their disease.

The median actual RTU rate was 28%. The lowest rates of utilization were in Ghana (9%) and the Philippines (10.3%), while the highest utilization rates were in Tunisia (46%) and Uruguay (37%).

Actual RTU rates were lower than optimal RTU rates for all 9 countries, with the smallest difference in Tunisia and the widest gap in Ghana—at nearly 43 percentage points.

The median level of unmet need was 47% for all countries combined.

Ghana and the Philippines had the highest levels of unmet need, at 82.3% and 80.5%, respectively. Costa Rica and Tunisia had the lowest levels of unmet need, at 25.5% and 18%, respectively.

The unmet need was especially high in countries with limited resources and a large population. The number of teletherapy machines per 1000 cancer cases ranged from a high of 1.3 in Tunisia to a low of 0.19 in Ghana.

The strong correlation between the actual RTU rates and the number of teletherapy machines per 1000 cancer cases/year in each country confirms that, although other access factors may be at play, the availability of RT machines is an important factor in RT utilization.

“Differences between optimal and actual RTU rates and the high percentage of unmet RT need likely stem from a number of complex reasons, although inadequate capacity for radiation therapy is the most obvious factor,” Dr Fidarova said.

“As obstacles in access to existing RT services—such as inadequate referral patterns, affordability of treatment, and geographical distribution of centers—differ by country, so does the ideal mix of solutions.”

Interim results of a phase 1/2 trial suggest KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, can be effective against aggressive non-Hodgkin lymphoma (NHL).

KTE-C19, administered after conditioning chemotherapy, produced an overall response rate (ORR) of

79% and a complete response (CR) rate of 52%.

However, the therapy also caused severe adverse events (AEs), and there were 2 deaths resulting from KTE-C19-related AEs.

Kite Pharma, Inc., the company developing KTE-C19, released these results and said additional data from this trial, known as ZUMA-1, will be submitted for presentation at an upcoming scientific meeting.

ZUMA-1 has enrolled patients with chemo-refractory, aggressive NHL. The phase 1 portion of the trial included 7 patients with diffuse large B-cell lymphoma (DLBCL).

Thus far, the phase 2 portion includes 62 NHL patients—51 with DLBCL and 11 with transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL).

The patients received a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, followed by a single infusion of KTE-C19 (at a target dose of 2 x 10⁶ CAR T cells/kg).

Responses

In the phase 1 portion of the trial (n=7), the initial ORR was 71%, and the CR rate was 57%. At 3 months of follow-up, the ORR and CR rate were both 43%. The response rates remained the same at 6 months and 9 months of follow-up.

In the phase 2 portion of the trial, for all 62 patients, the initial ORR was 79%, and the CR rate was 52%. At 3 months, the ORR was 44%, and the CR rate was 39%.

Among the 51 patients with DLBCL, the initial ORR was 76%, and the CR rate was 47%. At 3 months, the ORR was 39%, and the CR rate was 33%.

Among the 11 patients with TFL or PMBCL, the initial ORR was 91%, and the CR rate was 73%. At 3 months, the ORR and CR rates were 64%.

Longer follow-up data are not yet available for the phase 2 portion of the study.

Safety

For all 62 patients, the most common grade 3 or higher AEs were neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%), and encephalopathy (26%).

Grade 3 or higher cytokine release syndrome occurred in 18% of patients, and neurological toxicity occurred in 34%.

Two patients died from KTE-C19-related AEs—hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome.

Kite Pharma said the primary analysis from this study will include 101 patients with chemo-refractory NHL (DLBCL, TFL, and PMBCL), will have approximately 6 months of follow-up, and is expected in the first quarter of 2017.

ZUMA-1 is supported, in part, by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program.

Interim results of a phase 1/2 trial suggest KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, can be effective against aggressive non-Hodgkin lymphoma (NHL).

KTE-C19, administered after conditioning chemotherapy, produced an overall response rate (ORR) of

79% and a complete response (CR) rate of 52%.

However, the therapy also caused severe adverse events (AEs), and there were 2 deaths resulting from KTE-C19-related AEs.

Kite Pharma, Inc., the company developing KTE-C19, released these results and said additional data from this trial, known as ZUMA-1, will be submitted for presentation at an upcoming scientific meeting.

ZUMA-1 has enrolled patients with chemo-refractory, aggressive NHL. The phase 1 portion of the trial included 7 patients with diffuse large B-cell lymphoma (DLBCL).

Thus far, the phase 2 portion includes 62 NHL patients—51 with DLBCL and 11 with transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL).

The patients received a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, followed by a single infusion of KTE-C19 (at a target dose of 2 x 10⁶ CAR T cells/kg).

Responses

In the phase 1 portion of the trial (n=7), the initial ORR was 71%, and the CR rate was 57%. At 3 months of follow-up, the ORR and CR rate were both 43%. The response rates remained the same at 6 months and 9 months of follow-up.

In the phase 2 portion of the trial, for all 62 patients, the initial ORR was 79%, and the CR rate was 52%. At 3 months, the ORR was 44%, and the CR rate was 39%.

Among the 51 patients with DLBCL, the initial ORR was 76%, and the CR rate was 47%. At 3 months, the ORR was 39%, and the CR rate was 33%.

Among the 11 patients with TFL or PMBCL, the initial ORR was 91%, and the CR rate was 73%. At 3 months, the ORR and CR rates were 64%.

Longer follow-up data are not yet available for the phase 2 portion of the study.

Safety

For all 62 patients, the most common grade 3 or higher AEs were neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%), and encephalopathy (26%).

Grade 3 or higher cytokine release syndrome occurred in 18% of patients, and neurological toxicity occurred in 34%.

Two patients died from KTE-C19-related AEs—hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome.

Kite Pharma said the primary analysis from this study will include 101 patients with chemo-refractory NHL (DLBCL, TFL, and PMBCL), will have approximately 6 months of follow-up, and is expected in the first quarter of 2017.

ZUMA-1 is supported, in part, by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program.

Interim results of a phase 1/2 trial suggest KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, can be effective against aggressive non-Hodgkin lymphoma (NHL).

KTE-C19, administered after conditioning chemotherapy, produced an overall response rate (ORR) of

79% and a complete response (CR) rate of 52%.

However, the therapy also caused severe adverse events (AEs), and there were 2 deaths resulting from KTE-C19-related AEs.

Kite Pharma, Inc., the company developing KTE-C19, released these results and said additional data from this trial, known as ZUMA-1, will be submitted for presentation at an upcoming scientific meeting.

ZUMA-1 has enrolled patients with chemo-refractory, aggressive NHL. The phase 1 portion of the trial included 7 patients with diffuse large B-cell lymphoma (DLBCL).

Thus far, the phase 2 portion includes 62 NHL patients—51 with DLBCL and 11 with transformed follicular lymphoma (TFL) or primary mediastinal B-cell lymphoma (PMBCL).

The patients received a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, followed by a single infusion of KTE-C19 (at a target dose of 2 x 10⁶ CAR T cells/kg).

Responses

In the phase 1 portion of the trial (n=7), the initial ORR was 71%, and the CR rate was 57%. At 3 months of follow-up, the ORR and CR rate were both 43%. The response rates remained the same at 6 months and 9 months of follow-up.

In the phase 2 portion of the trial, for all 62 patients, the initial ORR was 79%, and the CR rate was 52%. At 3 months, the ORR was 44%, and the CR rate was 39%.

Among the 51 patients with DLBCL, the initial ORR was 76%, and the CR rate was 47%. At 3 months, the ORR was 39%, and the CR rate was 33%.

Among the 11 patients with TFL or PMBCL, the initial ORR was 91%, and the CR rate was 73%. At 3 months, the ORR and CR rates were 64%.

Longer follow-up data are not yet available for the phase 2 portion of the study.

Safety

For all 62 patients, the most common grade 3 or higher AEs were neutropenia (66%), anemia (40%), febrile neutropenia (29%), thrombocytopenia (29%), and encephalopathy (26%).

Grade 3 or higher cytokine release syndrome occurred in 18% of patients, and neurological toxicity occurred in 34%.

Two patients died from KTE-C19-related AEs—hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome.

Kite Pharma said the primary analysis from this study will include 101 patients with chemo-refractory NHL (DLBCL, TFL, and PMBCL), will have approximately 6 months of follow-up, and is expected in the first quarter of 2017.

ZUMA-1 is supported, in part, by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program.

Treatment recommendations for Waldenström macroglobulinemia have been updated based on the advice of a task force convened at the Eighth International Workshop on Waldenström Macroglobulinemia; the guidelines have been published in Blood.

The task force was impaneled to review recently published and ongoing clinical trial data as well as the impact of the newly recognized mutations MYD88 and CXCR4 on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives.

 

Michail Charakidis, David Joseph Russell/Wikimedia Commons/CC BY 2.0

Combinations of chemoimmunotherapy with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone continued to be indicated for most patients with the chronic, indolent, lymphoproliferative disorder, which is characterized by a high level of a macroglobulin and lymphoplasmacytic infiltrates in the bone marrow (Blood. 2016 Sep 8;128[10]:1321-8).

The panel reiterated that the criteria for initiating therapy include immunoglobulin M (IgM)-related complications and/or symptoms that are related to direct involvement of the bone marrow by tumor cells, constitutional symptoms, and bulky extramedullary disease. Patients presenting with symptoms that include symptomatic hyperviscosity, moderate to severe hemolytic anemia, and symptomatic cryoglobulinemia need immediate treatment.

Close observation is recommended for the subgroup of patients who do not really fulfill the criteria for a diagnosis of Waldenström macroglobulinemia (WM), and whose laboratory findings may be the only indicator of the presence of a progressive disease.

 

Treatment recommendations

For symptomatic patients in the first-line setting, “anti-CD20 monoclonal antibody therapy alone or in combination with chemotherapy is an important standard of care for most patients with WM,” the authors, led by Veronique Leblond, MD, of Pitié-Salpêtrière Hôpital, Paris, wrote.

Rituximab is frequently used in WM, either as monotherapy or in combination with chemotherapeutic agents. The panel cautions that rituximab as monotherapy should be avoided in patients with high IgM levels, because of a lower chance of response and the risk of an IgM flare.

In patients with high IgM levels (typically around 4,000 mg/dL), plasmapheresis can be initiated before rituximab therapy, and plasmapheresis should always and immediately be used when symptomatic hyperviscosity is present. However, plasmapheresis alone is not an effective treatment for WM and must be followed by a rapidly acting cytoreductive regimen.

Several rituximab combinations are recommended by the panel. These include:

• Dexamethasone-rituximab-cyclophosphamide, which is an active and safe option, has a manageable toxicity, and can be considered for frail patients who need combination therapy.

• Bendamustine-rituximab is effective for front-line treatment and is well tolerated even in elderly patients who experience limited episodes of myelosuppression and infections.

Other therapeutic regimens include bortezomib-based therapy, which is recommended for patients with high IgM levels, symptomatic hyperviscosity, cryoglobulinemia or cold agglutinemia, amyloidosis, and renal impairment or in young patients who prefer to avoid alkylator or nucleoside analogue therapy.

Another option is carfilzomib-based therapy, which is an emerging “neuropathy-sparing” regimen for proteasome-inhibitor–based therapy, although it may not be the best choice for elderly patients with preexisting cardiac conditions due to potential cardiac toxicity.

Ibrutinib has been approved as a primary therapy for patients who are not candidates for chemoimmunotherapy, but the authors point out that the optimal use of this agent is still being investigated.

“The aim of the first-line treatments is to reach a high response rate with a prolonged progression-free survival,” write the authors. “The panel agrees that there is need to perform clinical trials with chemotherapy-free combinations with new compounds alone or in combination with anti-CD20 antibodies.”

 

For symptomatic previously treated patients

The panel also offered recommendations for previously treated symptomatic patients who have relapsed or are refractory to treatment.

Any of the interventions recommended for symptomatic, untreated patients can be considered for those who have already gone through first line therapy. Retreatment can be considered with a specific intervention if a response was achieved for 2 or more years with that therapy, although they caution that patients who have progressed on first-line ibrutinib should not use it again.

Ofatumumab is a potential option for patients who are unable to tolerate rituximab, and nucleoside analogues can be considered in fit patients who have not responded to less-toxic treatments.

Another option in this setting is everolimus, although since it is associated with considerable toxicities, the best candidates for this drug are those who have not responded to or have progressed after multiple lines of other better-tolerated regimens.

Immunomodulatory agents can also be considered, but in the context of a clinical trial only, because of their potential adverse events.

Finally, the panel also agreed that stem cell transplantation should be discussed with select patients, and while it is a feasible and effective treatment option for high-risk WM patients, it should be ideally offered at early relapse.

 

Investigating B-cell receptor (BCR) pathway inhibitors along with existing and novel compounds in patients in the relapsed/refractory setting should be a priority, according to the panel.

“BCR inhibitors, combined with proteasome inhibitors, would be of interest for overcoming resistance by interfering with the two key pathways that are affected by MYD88,” wrote Dr. Leblond and coauthors.

Treatment recommendations for Waldenström macroglobulinemia have been updated based on the advice of a task force convened at the Eighth International Workshop on Waldenström Macroglobulinemia; the guidelines have been published in Blood.

The task force was impaneled to review recently published and ongoing clinical trial data as well as the impact of the newly recognized mutations MYD88 and CXCR4 on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives.

 

Michail Charakidis, David Joseph Russell/Wikimedia Commons/CC BY 2.0

Combinations of chemoimmunotherapy with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone continued to be indicated for most patients with the chronic, indolent, lymphoproliferative disorder, which is characterized by a high level of a macroglobulin and lymphoplasmacytic infiltrates in the bone marrow (Blood. 2016 Sep 8;128[10]:1321-8).

The panel reiterated that the criteria for initiating therapy include immunoglobulin M (IgM)-related complications and/or symptoms that are related to direct involvement of the bone marrow by tumor cells, constitutional symptoms, and bulky extramedullary disease. Patients presenting with symptoms that include symptomatic hyperviscosity, moderate to severe hemolytic anemia, and symptomatic cryoglobulinemia need immediate treatment.

Close observation is recommended for the subgroup of patients who do not really fulfill the criteria for a diagnosis of Waldenström macroglobulinemia (WM), and whose laboratory findings may be the only indicator of the presence of a progressive disease.

 

Treatment recommendations

For symptomatic patients in the first-line setting, “anti-CD20 monoclonal antibody therapy alone or in combination with chemotherapy is an important standard of care for most patients with WM,” the authors, led by Veronique Leblond, MD, of Pitié-Salpêtrière Hôpital, Paris, wrote.

Rituximab is frequently used in WM, either as monotherapy or in combination with chemotherapeutic agents. The panel cautions that rituximab as monotherapy should be avoided in patients with high IgM levels, because of a lower chance of response and the risk of an IgM flare.

In patients with high IgM levels (typically around 4,000 mg/dL), plasmapheresis can be initiated before rituximab therapy, and plasmapheresis should always and immediately be used when symptomatic hyperviscosity is present. However, plasmapheresis alone is not an effective treatment for WM and must be followed by a rapidly acting cytoreductive regimen.

Several rituximab combinations are recommended by the panel. These include:

• Dexamethasone-rituximab-cyclophosphamide, which is an active and safe option, has a manageable toxicity, and can be considered for frail patients who need combination therapy.

• Bendamustine-rituximab is effective for front-line treatment and is well tolerated even in elderly patients who experience limited episodes of myelosuppression and infections.

Other therapeutic regimens include bortezomib-based therapy, which is recommended for patients with high IgM levels, symptomatic hyperviscosity, cryoglobulinemia or cold agglutinemia, amyloidosis, and renal impairment or in young patients who prefer to avoid alkylator or nucleoside analogue therapy.

Another option is carfilzomib-based therapy, which is an emerging “neuropathy-sparing” regimen for proteasome-inhibitor–based therapy, although it may not be the best choice for elderly patients with preexisting cardiac conditions due to potential cardiac toxicity.

Ibrutinib has been approved as a primary therapy for patients who are not candidates for chemoimmunotherapy, but the authors point out that the optimal use of this agent is still being investigated.

“The aim of the first-line treatments is to reach a high response rate with a prolonged progression-free survival,” write the authors. “The panel agrees that there is need to perform clinical trials with chemotherapy-free combinations with new compounds alone or in combination with anti-CD20 antibodies.”

 

For symptomatic previously treated patients

The panel also offered recommendations for previously treated symptomatic patients who have relapsed or are refractory to treatment.

Any of the interventions recommended for symptomatic, untreated patients can be considered for those who have already gone through first line therapy. Retreatment can be considered with a specific intervention if a response was achieved for 2 or more years with that therapy, although they caution that patients who have progressed on first-line ibrutinib should not use it again.

Ofatumumab is a potential option for patients who are unable to tolerate rituximab, and nucleoside analogues can be considered in fit patients who have not responded to less-toxic treatments.

Another option in this setting is everolimus, although since it is associated with considerable toxicities, the best candidates for this drug are those who have not responded to or have progressed after multiple lines of other better-tolerated regimens.

Immunomodulatory agents can also be considered, but in the context of a clinical trial only, because of their potential adverse events.

Finally, the panel also agreed that stem cell transplantation should be discussed with select patients, and while it is a feasible and effective treatment option for high-risk WM patients, it should be ideally offered at early relapse.

 

Investigating B-cell receptor (BCR) pathway inhibitors along with existing and novel compounds in patients in the relapsed/refractory setting should be a priority, according to the panel.

“BCR inhibitors, combined with proteasome inhibitors, would be of interest for overcoming resistance by interfering with the two key pathways that are affected by MYD88,” wrote Dr. Leblond and coauthors.

Treatment recommendations for Waldenström macroglobulinemia have been updated based on the advice of a task force convened at the Eighth International Workshop on Waldenström Macroglobulinemia; the guidelines have been published in Blood.

The task force was impaneled to review recently published and ongoing clinical trial data as well as the impact of the newly recognized mutations MYD88 and CXCR4 on treatment decisions, indications for B-cell receptor and proteasome inhibitors, and future clinical trial initiatives.

 

Michail Charakidis, David Joseph Russell/Wikimedia Commons/CC BY 2.0

Combinations of chemoimmunotherapy with rituximab and cyclophosphamide-dexamethasone, bendamustine, or bortezomib-dexamethasone continued to be indicated for most patients with the chronic, indolent, lymphoproliferative disorder, which is characterized by a high level of a macroglobulin and lymphoplasmacytic infiltrates in the bone marrow (Blood. 2016 Sep 8;128[10]:1321-8).

The panel reiterated that the criteria for initiating therapy include immunoglobulin M (IgM)-related complications and/or symptoms that are related to direct involvement of the bone marrow by tumor cells, constitutional symptoms, and bulky extramedullary disease. Patients presenting with symptoms that include symptomatic hyperviscosity, moderate to severe hemolytic anemia, and symptomatic cryoglobulinemia need immediate treatment.

Close observation is recommended for the subgroup of patients who do not really fulfill the criteria for a diagnosis of Waldenström macroglobulinemia (WM), and whose laboratory findings may be the only indicator of the presence of a progressive disease.

 

Treatment recommendations

For symptomatic patients in the first-line setting, “anti-CD20 monoclonal antibody therapy alone or in combination with chemotherapy is an important standard of care for most patients with WM,” the authors, led by Veronique Leblond, MD, of Pitié-Salpêtrière Hôpital, Paris, wrote.

Rituximab is frequently used in WM, either as monotherapy or in combination with chemotherapeutic agents. The panel cautions that rituximab as monotherapy should be avoided in patients with high IgM levels, because of a lower chance of response and the risk of an IgM flare.

In patients with high IgM levels (typically around 4,000 mg/dL), plasmapheresis can be initiated before rituximab therapy, and plasmapheresis should always and immediately be used when symptomatic hyperviscosity is present. However, plasmapheresis alone is not an effective treatment for WM and must be followed by a rapidly acting cytoreductive regimen.

Several rituximab combinations are recommended by the panel. These include:

• Dexamethasone-rituximab-cyclophosphamide, which is an active and safe option, has a manageable toxicity, and can be considered for frail patients who need combination therapy.

• Bendamustine-rituximab is effective for front-line treatment and is well tolerated even in elderly patients who experience limited episodes of myelosuppression and infections.

Other therapeutic regimens include bortezomib-based therapy, which is recommended for patients with high IgM levels, symptomatic hyperviscosity, cryoglobulinemia or cold agglutinemia, amyloidosis, and renal impairment or in young patients who prefer to avoid alkylator or nucleoside analogue therapy.

Another option is carfilzomib-based therapy, which is an emerging “neuropathy-sparing” regimen for proteasome-inhibitor–based therapy, although it may not be the best choice for elderly patients with preexisting cardiac conditions due to potential cardiac toxicity.

Ibrutinib has been approved as a primary therapy for patients who are not candidates for chemoimmunotherapy, but the authors point out that the optimal use of this agent is still being investigated.

“The aim of the first-line treatments is to reach a high response rate with a prolonged progression-free survival,” write the authors. “The panel agrees that there is need to perform clinical trials with chemotherapy-free combinations with new compounds alone or in combination with anti-CD20 antibodies.”

 

For symptomatic previously treated patients

The panel also offered recommendations for previously treated symptomatic patients who have relapsed or are refractory to treatment.

Any of the interventions recommended for symptomatic, untreated patients can be considered for those who have already gone through first line therapy. Retreatment can be considered with a specific intervention if a response was achieved for 2 or more years with that therapy, although they caution that patients who have progressed on first-line ibrutinib should not use it again.

Ofatumumab is a potential option for patients who are unable to tolerate rituximab, and nucleoside analogues can be considered in fit patients who have not responded to less-toxic treatments.

Another option in this setting is everolimus, although since it is associated with considerable toxicities, the best candidates for this drug are those who have not responded to or have progressed after multiple lines of other better-tolerated regimens.

Immunomodulatory agents can also be considered, but in the context of a clinical trial only, because of their potential adverse events.

Finally, the panel also agreed that stem cell transplantation should be discussed with select patients, and while it is a feasible and effective treatment option for high-risk WM patients, it should be ideally offered at early relapse.

 

Investigating B-cell receptor (BCR) pathway inhibitors along with existing and novel compounds in patients in the relapsed/refractory setting should be a priority, according to the panel.

“BCR inhibitors, combined with proteasome inhibitors, would be of interest for overcoming resistance by interfering with the two key pathways that are affected by MYD88,” wrote Dr. Leblond and coauthors.

Patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) experienced improved Global Health Status/Quality of Life scale scores, compared with similar patients who received lenalidomide and dexamethasone (Rd) in the open-label, randomized, phase III ASPIRE trial.

In addition to the improved progression-free survival with KRd vs. Rd, which was previously reported (N Engl J Med. 2015 Jan 8;372[3]:142-52), 396 patients randomized to receive KRd had higher scores on the Global Health Status/Quality of Life (GHS/QoL) scale across 18 28-day treatment cycles, as compared with 396 patients randomized to receive Rd. Statistically significant differences were seen at cycle 12 when 25.5% of KRd-treated patients and 17.4% of Rd patients met the responder definition of at least a 5-point improvement on the GHS/QoL scale. At cycle 18, 24.2% vs. 12.9% of patients in the groups, respectively, met the responder definition, A. Keith Stewart, MD, of the Mayo Clinic in Scottsdale, Ariz., and his colleagues reported online ahead of print (J Clin Oncol. 2016 Sep. 6. doi: 10.1200/JCO.2016.66.9648).

At least a 15-point improvement was seen in 19.9% of KRd-treated patients and 12.4% of Rd-treated patients at cycle 12, and in 17.7% and 10.6%, respectively, at cycle 18. The minimal important difference of 5.6 points on the GHS/QoL scale was met at cycle 12 and was approached (4.8) at cycle 18, the researchers said.

The addition of carfilzomib to Rd improved health-related quality of life without negatively affecting patient-reported symptoms or increasing adverse treatment effects, they concluded.

Dr. Stewart reported consulting or advisory roles with several drug companies including Amgen, the maker of carfilzomib. Detailed disclosures for all authors are available with the full text of the article at JCO.org.

sworcester@frontlinemedcom.com

Patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) experienced improved Global Health Status/Quality of Life scale scores, compared with similar patients who received lenalidomide and dexamethasone (Rd) in the open-label, randomized, phase III ASPIRE trial.

In addition to the improved progression-free survival with KRd vs. Rd, which was previously reported (N Engl J Med. 2015 Jan 8;372[3]:142-52), 396 patients randomized to receive KRd had higher scores on the Global Health Status/Quality of Life (GHS/QoL) scale across 18 28-day treatment cycles, as compared with 396 patients randomized to receive Rd. Statistically significant differences were seen at cycle 12 when 25.5% of KRd-treated patients and 17.4% of Rd patients met the responder definition of at least a 5-point improvement on the GHS/QoL scale. At cycle 18, 24.2% vs. 12.9% of patients in the groups, respectively, met the responder definition, A. Keith Stewart, MD, of the Mayo Clinic in Scottsdale, Ariz., and his colleagues reported online ahead of print (J Clin Oncol. 2016 Sep. 6. doi: 10.1200/JCO.2016.66.9648).

At least a 15-point improvement was seen in 19.9% of KRd-treated patients and 12.4% of Rd-treated patients at cycle 12, and in 17.7% and 10.6%, respectively, at cycle 18. The minimal important difference of 5.6 points on the GHS/QoL scale was met at cycle 12 and was approached (4.8) at cycle 18, the researchers said.

The addition of carfilzomib to Rd improved health-related quality of life without negatively affecting patient-reported symptoms or increasing adverse treatment effects, they concluded.

Dr. Stewart reported consulting or advisory roles with several drug companies including Amgen, the maker of carfilzomib. Detailed disclosures for all authors are available with the full text of the article at JCO.org.

sworcester@frontlinemedcom.com

Patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) experienced improved Global Health Status/Quality of Life scale scores, compared with similar patients who received lenalidomide and dexamethasone (Rd) in the open-label, randomized, phase III ASPIRE trial.

In addition to the improved progression-free survival with KRd vs. Rd, which was previously reported (N Engl J Med. 2015 Jan 8;372[3]:142-52), 396 patients randomized to receive KRd had higher scores on the Global Health Status/Quality of Life (GHS/QoL) scale across 18 28-day treatment cycles, as compared with 396 patients randomized to receive Rd. Statistically significant differences were seen at cycle 12 when 25.5% of KRd-treated patients and 17.4% of Rd patients met the responder definition of at least a 5-point improvement on the GHS/QoL scale. At cycle 18, 24.2% vs. 12.9% of patients in the groups, respectively, met the responder definition, A. Keith Stewart, MD, of the Mayo Clinic in Scottsdale, Ariz., and his colleagues reported online ahead of print (J Clin Oncol. 2016 Sep. 6. doi: 10.1200/JCO.2016.66.9648).

At least a 15-point improvement was seen in 19.9% of KRd-treated patients and 12.4% of Rd-treated patients at cycle 12, and in 17.7% and 10.6%, respectively, at cycle 18. The minimal important difference of 5.6 points on the GHS/QoL scale was met at cycle 12 and was approached (4.8) at cycle 18, the researchers said.

The addition of carfilzomib to Rd improved health-related quality of life without negatively affecting patient-reported symptoms or increasing adverse treatment effects, they concluded.

Dr. Stewart reported consulting or advisory roles with several drug companies including Amgen, the maker of carfilzomib. Detailed disclosures for all authors are available with the full text of the article at JCO.org.

sworcester@frontlinemedcom.com

Researchers say they have discovered a type of macrophage that may protect against lung infections during chemotherapy.

These macrophages, found in the lungs of mice, were able to survive chemotherapy.

The macrophages could remove bacteria when activated by a vaccine, which improved survival in mice with lethal bacterial pneumonia that had received chemotherapy and were therefore depleted of neutrophils.

The researchers said these results suggest the cells—known as vaccine-induced macrophages (ViMs)— might be able to protect cancer patients from life-threatening infections.

“We have identified a new form of housekeeping macrophage in mice that may, in future, be harnessed to protect against lung infections—like bacterial pneumonia—that remain one of the greatest threats to survival of cancer patients during chemotherapy,” said Peter Murray, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Murray and his colleagues detailed this discovery in PNAS.

Working in a mouse model that mimics infection in chemotherapy-treated patients, the researchers found that vaccination protected mice from Pseudomonas aeruginosa pneumonia.

The quest to understand how such protection was possible in the absence of neutrophils led the team to discover ViMs.

The researchers found that ViMs were produced in the lungs following vaccination, proliferated locally, and could persist for at least a month.

Analyses suggested ViMs are closely related to alveolar macrophages, which originate in the embryo, reside in the air-exposed surfaces of alveoli, and are self-maintained in adults.

“All lines of cellular and molecular evidence in this study point to alveolar macrophages as the source of ViMs,” Dr Murray said.

However, unlike alveolar macrophages, the population of ViMs remained stable during chemotherapy and exhibited enhanced phagocytic activity.

When ViMs were transferred to unvaccinated mice depleted of neutrophils via chemotherapy, the animals were protected from lethal Pseudomonas infections.

“We now know that increasing the number of ViMs in the tissue can compensate for the immune deficit caused by chemotherapy,” said study author Akinobu Kamei, MD, of St. Jude Children’s Research Hospital.

“In this study, we relied on vaccination prior to chemotherapy. Going forward, we will explore other, more practical methods for use at the bedside to effectively induce tissue-resident macrophages like ViMs.”

The possible approaches include using drugs or cytokines to induce protection in the immune-compromised host.

Researchers say they have discovered a type of macrophage that may protect against lung infections during chemotherapy.

These macrophages, found in the lungs of mice, were able to survive chemotherapy.

The macrophages could remove bacteria when activated by a vaccine, which improved survival in mice with lethal bacterial pneumonia that had received chemotherapy and were therefore depleted of neutrophils.

The researchers said these results suggest the cells—known as vaccine-induced macrophages (ViMs)— might be able to protect cancer patients from life-threatening infections.

“We have identified a new form of housekeeping macrophage in mice that may, in future, be harnessed to protect against lung infections—like bacterial pneumonia—that remain one of the greatest threats to survival of cancer patients during chemotherapy,” said Peter Murray, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Murray and his colleagues detailed this discovery in PNAS.

Working in a mouse model that mimics infection in chemotherapy-treated patients, the researchers found that vaccination protected mice from Pseudomonas aeruginosa pneumonia.

The quest to understand how such protection was possible in the absence of neutrophils led the team to discover ViMs.

The researchers found that ViMs were produced in the lungs following vaccination, proliferated locally, and could persist for at least a month.

Analyses suggested ViMs are closely related to alveolar macrophages, which originate in the embryo, reside in the air-exposed surfaces of alveoli, and are self-maintained in adults.

“All lines of cellular and molecular evidence in this study point to alveolar macrophages as the source of ViMs,” Dr Murray said.

However, unlike alveolar macrophages, the population of ViMs remained stable during chemotherapy and exhibited enhanced phagocytic activity.

When ViMs were transferred to unvaccinated mice depleted of neutrophils via chemotherapy, the animals were protected from lethal Pseudomonas infections.

“We now know that increasing the number of ViMs in the tissue can compensate for the immune deficit caused by chemotherapy,” said study author Akinobu Kamei, MD, of St. Jude Children’s Research Hospital.

“In this study, we relied on vaccination prior to chemotherapy. Going forward, we will explore other, more practical methods for use at the bedside to effectively induce tissue-resident macrophages like ViMs.”

The possible approaches include using drugs or cytokines to induce protection in the immune-compromised host.

Researchers say they have discovered a type of macrophage that may protect against lung infections during chemotherapy.

These macrophages, found in the lungs of mice, were able to survive chemotherapy.

The macrophages could remove bacteria when activated by a vaccine, which improved survival in mice with lethal bacterial pneumonia that had received chemotherapy and were therefore depleted of neutrophils.

The researchers said these results suggest the cells—known as vaccine-induced macrophages (ViMs)— might be able to protect cancer patients from life-threatening infections.

“We have identified a new form of housekeeping macrophage in mice that may, in future, be harnessed to protect against lung infections—like bacterial pneumonia—that remain one of the greatest threats to survival of cancer patients during chemotherapy,” said Peter Murray, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Murray and his colleagues detailed this discovery in PNAS.

Working in a mouse model that mimics infection in chemotherapy-treated patients, the researchers found that vaccination protected mice from Pseudomonas aeruginosa pneumonia.

The quest to understand how such protection was possible in the absence of neutrophils led the team to discover ViMs.

The researchers found that ViMs were produced in the lungs following vaccination, proliferated locally, and could persist for at least a month.

Analyses suggested ViMs are closely related to alveolar macrophages, which originate in the embryo, reside in the air-exposed surfaces of alveoli, and are self-maintained in adults.

“All lines of cellular and molecular evidence in this study point to alveolar macrophages as the source of ViMs,” Dr Murray said.

However, unlike alveolar macrophages, the population of ViMs remained stable during chemotherapy and exhibited enhanced phagocytic activity.

When ViMs were transferred to unvaccinated mice depleted of neutrophils via chemotherapy, the animals were protected from lethal Pseudomonas infections.

“We now know that increasing the number of ViMs in the tissue can compensate for the immune deficit caused by chemotherapy,” said study author Akinobu Kamei, MD, of St. Jude Children’s Research Hospital.

“In this study, we relied on vaccination prior to chemotherapy. Going forward, we will explore other, more practical methods for use at the bedside to effectively induce tissue-resident macrophages like ViMs.”

The possible approaches include using drugs or cytokines to induce protection in the immune-compromised host.