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MF assessment and treatment an ‘evolution’ from the past
© ASCO/Zach Boyden-Holmes
NEW YORK—The 11th NCCN Congress: Hematologic Malignancies coincided with the release of the inaugural edition of the NCCN treatment guideline on myeloproliferative neoplasms (MPNs), and Ruben A. Mesa, MD, took the opportunity to discuss the framework of the document and the evolving management of MPNs.
Dr Mesa, of the Mayo Clinic Cancer Center in Arizona, is the chair of the MPN guideline committee.
This initial version of the guideline focuses on the workup and diagnosis of primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF, and treatment guidelines for MF.
The committee decided to first tackle the treatment guidelines in MF because, as Dr Mesa explained, MF is “the most severe of the MPNs with the most unmet needs in terms of guidance.”
Treatment guidelines for polycythemia vera (PV) and essential thrombocythemia (ET) will be forthcoming in 2017, he said, as well as diagnosis and treatment of atypical MPNs, such as hypereosinophilic syndrome and systemic mast cell disease.
Workup of an MPN
The guideline committee focused on information regarding diagnosis—the time and place to consider bone marrow biopsies, when to use cytogenetics, and when to perform next-generation sequencing.
They stressed the importance of quantifying disease burden and utilizing the now-validated symptom assessment tools, particularly in MF.
“Finally, we leveraged the many prognostic scoring systems that have been developed for these diseases, particularly IPSS for myelofibrosis at diagnosis or the DIPSS and DIPSS-plus at subsequent time points,” Dr Mesa said.
In addition to clinical-based prognostic scoring systems, information regarding molecular features and their impact is evolving, he said.
The guideline provides a table of mutations with prognostic significance. JAK2, MPL, or CALR mutations are “brighter mutations,” he said, while adverse prognostic markers include ASXL1, EZH2, IDH1/2, SRSF2, and TP53.
“All of these have some significant prognostic implications in primary myelofibrosis, specifically,” he said.
Assessing MPN burden
“When treating these patients, it’s important to be mindful of the overall burden of the disease,” Dr Mesa said.
He called this emphasis on disease burden “an evolution from the past, where therapy was either supportive or primarily focused on prevention of thrombosis with ET or PV.”
Practitioners need to be additionally mindful of the risk of vascular events, progression, the impact of cytopenias, splenomegaly, the burden of symptoms, and the baseline degree of comorbidities.
“[W]e encourage the use of validated symptom tools that have been used now in the majority of clinical trials in this setting,” Dr Mesa added.
The MPN-10 assessment tool, included in the guideline, evaluates 10 symptoms—early satiety, abdominal discomfort, inactivity, problems concentrating, numbness/tingling, night sweats, itching, bone pain, fever, and unintentional weight loss—on a scale of 0 to 10.
Patients with MF are the most symptomatic, Dr Mesa commented, although “it is notable how frequent symptoms are present in patients with PV and ET.”
Response criteria
For a complete response, individuals must have marked improvement to near normalization in both bone marrow and peripheral blood in addition to resolution of their disease symptoms.
Partial response is basically “just shy” of the complete response level, Dr Mesa said, with bone marrow resolution not being required.
The guideline also outlines response criteria for progressive, stable, and relapsed disease, clinical improvement, and anemia, spleen, and symptom response.
“But I’ll highlight that the majority of the responses that are received currently with medical therapy are in the area of clinical improvement,” Dr Mesa said.
Treatment guidance
Specific treatment guidelines for low-risk, intermediate-1 risk, intermediate-2- or high-risk MF from the new guideline have been described in an earlier article and will not be discussed here.
Of note, however, Dr Mesa explained that ruxolitinib is a very important part of the treatment guideline because it is the only therapy approved by the US Food and Drug Administration (FDA) to treat MF.
“Over time, it’s been shown that there is an improvement in survival [with ruxolitinib],” Dr Mesa said, perhaps because of a decrease with treatment in the morbidity and the debilitation of patients.
Investigators presented the 5-year update of this information at ASCO 2016 and reported that patients maintained reduction in splenomegaly up through 5 years, both in those randomized to ruxolitinib and those crossing over from placebo.
“Long-term, we clearly looked to see whether there was a signal of new onset or late onset toxicities,” Dr Mesa said, which largely was not the case. "Toxicities have been well described in earlier studies, primarily around anemia, thrombocytopenia, and mild constitutional symptoms.”
However, long-term therapy increases the rate of development of shingles and non-melanoma skin cancer. Rates of transformation to acute myeloid leukemia were consistent with those published for similar patient populations with MF.
“If I see a patient stable on ruxolitinib who has a marked drop in their counts later on in the course of their disease,” Dr Mesa added, “I’m certainly suspicious of progression.”
He also works them up for other causes of anemia if it evolves out of the blue.
Support in MF-related anemia
“With anemia, we’re mindful of iron stores, EPO level, and being certain there’s not the presence of hemolysis or other contributors,” Dr Mesa said.
The guideline recommends stratifying patients based on serum EPO levels—those with less than 500 mU/mL and those with 500 mU/mL and higher.
“If we lower the EPO level, the greater the likelihood of response,” Dr Mesa said. “In my experience, the lower the transfusion burden, the greater the likelihood of response.”
Other than erythropoiesis-stimulating agents for individuals with lower serum levels, androgens and immunomodulatory drugs for those with higher levels have some benefit.
But “they all have their limitations,” Dr Mesa said, and “they tend to range in benefit from 20% to 30%.”
The future
Dr Mesa discussed a few agents in the pipeline that “might impact these guidelines,” such as the JAK2/FLT3 inhibitor pacritinib and the JAK1/JAK2 inhibitor momelotinib.
Pacritinib had a positive phase 3 study, but the mortality rate was higher than expected, and it was put on an FDA hold.
Data from a second phase 3 study (PERSIST-1) will be reviewed in the aggregate to evaluate the benefit of pacritinib and whether the mortality rate was associated with drug-related side effects or adverse patient selection, “which we suspect might be the case,” Dr Mesa said.
“This agent may come off hold, depending upon the data of that second phase 3 study,” he added.
Momelotinib is also in an advanced phase 3 program with 2 trials underway. Both trials have completed accrual.
One is an upfront study of momelotinib versus ruxolitinib (NCT01969838). The goal is to reduce anemia without inferiority of splenomegaly and MPN symptoms.
The other phase 3 momelotinib trial is a second-line study versus best alternative therapy, including ruxoltinib (NCT02101268).
Combination studies are ongoing with a ruxolitinib base and a variety of secondary agents, including danazol, pomalidomide, PEG IFN α2a, 5-AZA, panobinostat, BKM-120, and LDE-225. All agents appear to achieve improvement in splenomegaly and symptoms.
But “incremental benefit over ruxolitinib alone is not yet clear,” Dr Mesa said. “I would say there’s not yet a recommended off-label combination which is widely being used.”
Dr Mesa also highlighted PRM-151, an antifibrosing drug that had a favorable early stage study with several doses, and the telomerase inhibitor imetelstat, which had a deep set of molecular responses in about a third of patients with MF. Imetelstat is currently being evaluated in the second-line setting (NCT02426086).
Regarding the possible positioning of new therapies, Dr Mesa believes “momelotinib and pacritinib may play a role in front-line, depending on the final data from those studies.”
“In second-line for MF—this is where most of the activity is in the trials,” he said. “Momelotinib, pacritinib, PRM-151, and imetelstat have possibilities.” 
© ASCO/Zach Boyden-Holmes
NEW YORK—The 11th NCCN Congress: Hematologic Malignancies coincided with the release of the inaugural edition of the NCCN treatment guideline on myeloproliferative neoplasms (MPNs), and Ruben A. Mesa, MD, took the opportunity to discuss the framework of the document and the evolving management of MPNs.
Dr Mesa, of the Mayo Clinic Cancer Center in Arizona, is the chair of the MPN guideline committee.
This initial version of the guideline focuses on the workup and diagnosis of primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF, and treatment guidelines for MF.
The committee decided to first tackle the treatment guidelines in MF because, as Dr Mesa explained, MF is “the most severe of the MPNs with the most unmet needs in terms of guidance.”
Treatment guidelines for polycythemia vera (PV) and essential thrombocythemia (ET) will be forthcoming in 2017, he said, as well as diagnosis and treatment of atypical MPNs, such as hypereosinophilic syndrome and systemic mast cell disease.
Workup of an MPN
The guideline committee focused on information regarding diagnosis—the time and place to consider bone marrow biopsies, when to use cytogenetics, and when to perform next-generation sequencing.
They stressed the importance of quantifying disease burden and utilizing the now-validated symptom assessment tools, particularly in MF.
“Finally, we leveraged the many prognostic scoring systems that have been developed for these diseases, particularly IPSS for myelofibrosis at diagnosis or the DIPSS and DIPSS-plus at subsequent time points,” Dr Mesa said.
In addition to clinical-based prognostic scoring systems, information regarding molecular features and their impact is evolving, he said.
The guideline provides a table of mutations with prognostic significance. JAK2, MPL, or CALR mutations are “brighter mutations,” he said, while adverse prognostic markers include ASXL1, EZH2, IDH1/2, SRSF2, and TP53.
“All of these have some significant prognostic implications in primary myelofibrosis, specifically,” he said.
Assessing MPN burden
“When treating these patients, it’s important to be mindful of the overall burden of the disease,” Dr Mesa said.
He called this emphasis on disease burden “an evolution from the past, where therapy was either supportive or primarily focused on prevention of thrombosis with ET or PV.”
Practitioners need to be additionally mindful of the risk of vascular events, progression, the impact of cytopenias, splenomegaly, the burden of symptoms, and the baseline degree of comorbidities.
“[W]e encourage the use of validated symptom tools that have been used now in the majority of clinical trials in this setting,” Dr Mesa added.
The MPN-10 assessment tool, included in the guideline, evaluates 10 symptoms—early satiety, abdominal discomfort, inactivity, problems concentrating, numbness/tingling, night sweats, itching, bone pain, fever, and unintentional weight loss—on a scale of 0 to 10.
Patients with MF are the most symptomatic, Dr Mesa commented, although “it is notable how frequent symptoms are present in patients with PV and ET.”
Response criteria
For a complete response, individuals must have marked improvement to near normalization in both bone marrow and peripheral blood in addition to resolution of their disease symptoms.
Partial response is basically “just shy” of the complete response level, Dr Mesa said, with bone marrow resolution not being required.
The guideline also outlines response criteria for progressive, stable, and relapsed disease, clinical improvement, and anemia, spleen, and symptom response.
“But I’ll highlight that the majority of the responses that are received currently with medical therapy are in the area of clinical improvement,” Dr Mesa said.
Treatment guidance
Specific treatment guidelines for low-risk, intermediate-1 risk, intermediate-2- or high-risk MF from the new guideline have been described in an earlier article and will not be discussed here.
Of note, however, Dr Mesa explained that ruxolitinib is a very important part of the treatment guideline because it is the only therapy approved by the US Food and Drug Administration (FDA) to treat MF.
“Over time, it’s been shown that there is an improvement in survival [with ruxolitinib],” Dr Mesa said, perhaps because of a decrease with treatment in the morbidity and the debilitation of patients.
Investigators presented the 5-year update of this information at ASCO 2016 and reported that patients maintained reduction in splenomegaly up through 5 years, both in those randomized to ruxolitinib and those crossing over from placebo.
“Long-term, we clearly looked to see whether there was a signal of new onset or late onset toxicities,” Dr Mesa said, which largely was not the case. "Toxicities have been well described in earlier studies, primarily around anemia, thrombocytopenia, and mild constitutional symptoms.”
However, long-term therapy increases the rate of development of shingles and non-melanoma skin cancer. Rates of transformation to acute myeloid leukemia were consistent with those published for similar patient populations with MF.
“If I see a patient stable on ruxolitinib who has a marked drop in their counts later on in the course of their disease,” Dr Mesa added, “I’m certainly suspicious of progression.”
He also works them up for other causes of anemia if it evolves out of the blue.
Support in MF-related anemia
“With anemia, we’re mindful of iron stores, EPO level, and being certain there’s not the presence of hemolysis or other contributors,” Dr Mesa said.
The guideline recommends stratifying patients based on serum EPO levels—those with less than 500 mU/mL and those with 500 mU/mL and higher.
“If we lower the EPO level, the greater the likelihood of response,” Dr Mesa said. “In my experience, the lower the transfusion burden, the greater the likelihood of response.”
Other than erythropoiesis-stimulating agents for individuals with lower serum levels, androgens and immunomodulatory drugs for those with higher levels have some benefit.
But “they all have their limitations,” Dr Mesa said, and “they tend to range in benefit from 20% to 30%.”
The future
Dr Mesa discussed a few agents in the pipeline that “might impact these guidelines,” such as the JAK2/FLT3 inhibitor pacritinib and the JAK1/JAK2 inhibitor momelotinib.
Pacritinib had a positive phase 3 study, but the mortality rate was higher than expected, and it was put on an FDA hold.
Data from a second phase 3 study (PERSIST-1) will be reviewed in the aggregate to evaluate the benefit of pacritinib and whether the mortality rate was associated with drug-related side effects or adverse patient selection, “which we suspect might be the case,” Dr Mesa said.
“This agent may come off hold, depending upon the data of that second phase 3 study,” he added.
Momelotinib is also in an advanced phase 3 program with 2 trials underway. Both trials have completed accrual.
One is an upfront study of momelotinib versus ruxolitinib (NCT01969838). The goal is to reduce anemia without inferiority of splenomegaly and MPN symptoms.
The other phase 3 momelotinib trial is a second-line study versus best alternative therapy, including ruxoltinib (NCT02101268).
Combination studies are ongoing with a ruxolitinib base and a variety of secondary agents, including danazol, pomalidomide, PEG IFN α2a, 5-AZA, panobinostat, BKM-120, and LDE-225. All agents appear to achieve improvement in splenomegaly and symptoms.
But “incremental benefit over ruxolitinib alone is not yet clear,” Dr Mesa said. “I would say there’s not yet a recommended off-label combination which is widely being used.”
Dr Mesa also highlighted PRM-151, an antifibrosing drug that had a favorable early stage study with several doses, and the telomerase inhibitor imetelstat, which had a deep set of molecular responses in about a third of patients with MF. Imetelstat is currently being evaluated in the second-line setting (NCT02426086).
Regarding the possible positioning of new therapies, Dr Mesa believes “momelotinib and pacritinib may play a role in front-line, depending on the final data from those studies.”
“In second-line for MF—this is where most of the activity is in the trials,” he said. “Momelotinib, pacritinib, PRM-151, and imetelstat have possibilities.”
© ASCO/Zach Boyden-Holmes
NEW YORK—The 11th NCCN Congress: Hematologic Malignancies coincided with the release of the inaugural edition of the NCCN treatment guideline on myeloproliferative neoplasms (MPNs), and Ruben A. Mesa, MD, took the opportunity to discuss the framework of the document and the evolving management of MPNs.
Dr Mesa, of the Mayo Clinic Cancer Center in Arizona, is the chair of the MPN guideline committee.
This initial version of the guideline focuses on the workup and diagnosis of primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF, and treatment guidelines for MF.
The committee decided to first tackle the treatment guidelines in MF because, as Dr Mesa explained, MF is “the most severe of the MPNs with the most unmet needs in terms of guidance.”
Treatment guidelines for polycythemia vera (PV) and essential thrombocythemia (ET) will be forthcoming in 2017, he said, as well as diagnosis and treatment of atypical MPNs, such as hypereosinophilic syndrome and systemic mast cell disease.
Workup of an MPN
The guideline committee focused on information regarding diagnosis—the time and place to consider bone marrow biopsies, when to use cytogenetics, and when to perform next-generation sequencing.
They stressed the importance of quantifying disease burden and utilizing the now-validated symptom assessment tools, particularly in MF.
“Finally, we leveraged the many prognostic scoring systems that have been developed for these diseases, particularly IPSS for myelofibrosis at diagnosis or the DIPSS and DIPSS-plus at subsequent time points,” Dr Mesa said.
In addition to clinical-based prognostic scoring systems, information regarding molecular features and their impact is evolving, he said.
The guideline provides a table of mutations with prognostic significance. JAK2, MPL, or CALR mutations are “brighter mutations,” he said, while adverse prognostic markers include ASXL1, EZH2, IDH1/2, SRSF2, and TP53.
“All of these have some significant prognostic implications in primary myelofibrosis, specifically,” he said.
Assessing MPN burden
“When treating these patients, it’s important to be mindful of the overall burden of the disease,” Dr Mesa said.
He called this emphasis on disease burden “an evolution from the past, where therapy was either supportive or primarily focused on prevention of thrombosis with ET or PV.”
Practitioners need to be additionally mindful of the risk of vascular events, progression, the impact of cytopenias, splenomegaly, the burden of symptoms, and the baseline degree of comorbidities.
“[W]e encourage the use of validated symptom tools that have been used now in the majority of clinical trials in this setting,” Dr Mesa added.
The MPN-10 assessment tool, included in the guideline, evaluates 10 symptoms—early satiety, abdominal discomfort, inactivity, problems concentrating, numbness/tingling, night sweats, itching, bone pain, fever, and unintentional weight loss—on a scale of 0 to 10.
Patients with MF are the most symptomatic, Dr Mesa commented, although “it is notable how frequent symptoms are present in patients with PV and ET.”
Response criteria
For a complete response, individuals must have marked improvement to near normalization in both bone marrow and peripheral blood in addition to resolution of their disease symptoms.
Partial response is basically “just shy” of the complete response level, Dr Mesa said, with bone marrow resolution not being required.
The guideline also outlines response criteria for progressive, stable, and relapsed disease, clinical improvement, and anemia, spleen, and symptom response.
“But I’ll highlight that the majority of the responses that are received currently with medical therapy are in the area of clinical improvement,” Dr Mesa said.
Treatment guidance
Specific treatment guidelines for low-risk, intermediate-1 risk, intermediate-2- or high-risk MF from the new guideline have been described in an earlier article and will not be discussed here.
Of note, however, Dr Mesa explained that ruxolitinib is a very important part of the treatment guideline because it is the only therapy approved by the US Food and Drug Administration (FDA) to treat MF.
“Over time, it’s been shown that there is an improvement in survival [with ruxolitinib],” Dr Mesa said, perhaps because of a decrease with treatment in the morbidity and the debilitation of patients.
Investigators presented the 5-year update of this information at ASCO 2016 and reported that patients maintained reduction in splenomegaly up through 5 years, both in those randomized to ruxolitinib and those crossing over from placebo.
“Long-term, we clearly looked to see whether there was a signal of new onset or late onset toxicities,” Dr Mesa said, which largely was not the case. "Toxicities have been well described in earlier studies, primarily around anemia, thrombocytopenia, and mild constitutional symptoms.”
However, long-term therapy increases the rate of development of shingles and non-melanoma skin cancer. Rates of transformation to acute myeloid leukemia were consistent with those published for similar patient populations with MF.
“If I see a patient stable on ruxolitinib who has a marked drop in their counts later on in the course of their disease,” Dr Mesa added, “I’m certainly suspicious of progression.”
He also works them up for other causes of anemia if it evolves out of the blue.
Support in MF-related anemia
“With anemia, we’re mindful of iron stores, EPO level, and being certain there’s not the presence of hemolysis or other contributors,” Dr Mesa said.
The guideline recommends stratifying patients based on serum EPO levels—those with less than 500 mU/mL and those with 500 mU/mL and higher.
“If we lower the EPO level, the greater the likelihood of response,” Dr Mesa said. “In my experience, the lower the transfusion burden, the greater the likelihood of response.”
Other than erythropoiesis-stimulating agents for individuals with lower serum levels, androgens and immunomodulatory drugs for those with higher levels have some benefit.
But “they all have their limitations,” Dr Mesa said, and “they tend to range in benefit from 20% to 30%.”
The future
Dr Mesa discussed a few agents in the pipeline that “might impact these guidelines,” such as the JAK2/FLT3 inhibitor pacritinib and the JAK1/JAK2 inhibitor momelotinib.
Pacritinib had a positive phase 3 study, but the mortality rate was higher than expected, and it was put on an FDA hold.
Data from a second phase 3 study (PERSIST-1) will be reviewed in the aggregate to evaluate the benefit of pacritinib and whether the mortality rate was associated with drug-related side effects or adverse patient selection, “which we suspect might be the case,” Dr Mesa said.
“This agent may come off hold, depending upon the data of that second phase 3 study,” he added.
Momelotinib is also in an advanced phase 3 program with 2 trials underway. Both trials have completed accrual.
One is an upfront study of momelotinib versus ruxolitinib (NCT01969838). The goal is to reduce anemia without inferiority of splenomegaly and MPN symptoms.
The other phase 3 momelotinib trial is a second-line study versus best alternative therapy, including ruxoltinib (NCT02101268).
Combination studies are ongoing with a ruxolitinib base and a variety of secondary agents, including danazol, pomalidomide, PEG IFN α2a, 5-AZA, panobinostat, BKM-120, and LDE-225. All agents appear to achieve improvement in splenomegaly and symptoms.
But “incremental benefit over ruxolitinib alone is not yet clear,” Dr Mesa said. “I would say there’s not yet a recommended off-label combination which is widely being used.”
Dr Mesa also highlighted PRM-151, an antifibrosing drug that had a favorable early stage study with several doses, and the telomerase inhibitor imetelstat, which had a deep set of molecular responses in about a third of patients with MF. Imetelstat is currently being evaluated in the second-line setting (NCT02426086).
Regarding the possible positioning of new therapies, Dr Mesa believes “momelotinib and pacritinib may play a role in front-line, depending on the final data from those studies.”
“In second-line for MF—this is where most of the activity is in the trials,” he said. “Momelotinib, pacritinib, PRM-151, and imetelstat have possibilities.”
Supportive care isn’t palliative care, speaker says
Photo courtesy of NCI
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.
Photo courtesy of NCI
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.
Photo courtesy of NCI
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.
Speaker outlines importance of cell of origin in DLBCL
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.”
‘Practice-changing’ treatments emerging in AML
NEW YORK—We are “finally” making progress in the treatment of acute myeloid leukemia (AML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
Jessica K. Altman, MD, said a number of developments have resulted in improved AML treatment, including a better understanding of biology and prognostic assessment, continued advances in transplant, and updating standard treatments and incorporating novel agents in both relapsed/refractory and newly diagnosed patients.
“There are a couple of practice-changing treatments in acute myeloid leukemia, 2 of which happened over the last decade: daunorubicin intensification and the use of FLT3 inhibitors,” said Dr Altman, an associate professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Dr Altman went on to explain that novel therapies for AML can be divided into 2 basic categories. There are agents that don’t depend on mutation status (like daunorubicin) and those that are mutation-specific (like FLT3 inhibitors).
Therapies not dependent on mutational complexity
The therapies that are not dependent on mutational complexity include anti-CD33 antibodies, BCL‐2 inhibitors, a dose-intensified anthracycline regimen, and different formulations of 7+3, including CPX‐351.
Escalated daunorubicin
Randomized trials of escalated daunorubicin (90 vs 45 mg/m2) have demonstrated benefit in complete responses (CRs) and overall survival (OS) in intermediate-risk patients and patients with core-binding factor mutation. They have demonstrated benefit in OS in FLT3 ITD+ patients.
In patients up to 65 years of age, 60–90 mg/m2 of daunorubicin is now standard.
“It’s still not clear to me—and I don’t know if it ever will be—if 90 is equivalent to 60,” Dr Altman said.
CPX-351
CPX-351 is a liposomal formulation of cytarabine and daunorubicin. In a randomized, phase 3 study of older adults with secondary AML, the median OS was 9.56 months for patients treated with CPX-351 and 5.95 months for patients on the 7+3 regimen (P=0.005).
The median event-free survival was significantly better with CPX-351 (P=0.021), as was the rate of CR + CR with incomplete blood count recovery (CRi). The rate of CR + CRi was 47.7% with CPX-351 and 33.3% for 7+3 (P=0.016).
A similar number of patients went on to transplant in each arm. Grade 3-5 adverse events were similar in frequency and severity in both arms—92% with CPX-351 vs 91% with 7+3.
SGN-CD33A
CD33 is not a new target in myeloid leukemia, Dr Altman pointed out. Gemtuzumab ozogamicin has been studied, approved by the US Food and Drug Administration, and then withdrawn.
However, an increasing number of studies with gemtuzumab are underway, she said, and the agent may once again have a place in the AML armamentarium.
The newest CD33 construct is SGN-CD33A, a stable dipeptide linker that enables uniform drug loading of a pyrrolobenzodiazepine dimer that crosslinks DNA and leads to cell death.
“Single-agent data was quite promising,” Dr Altman noted, with a CR + CRi rate of 41% in previously treated patients and 58% in 12 treatment-naïve patients.
These results prompted a combination study of SGN-CD33A with hypomethylating agents.
“Results were higher than expected with a hypomethylating agent,” Dr Altman pointed out.
The CR + CRi + CR with incomplete platelet recovery was 58%. And the median relapse-free survival was 7.7 months.
A phase 3 randomized trial of SGN-CD33A is planned.
Venetoclax
BCL-2 inhibitors are the fourth type of agent not dependent on mutation complexity. Venetoclax (ABT‐199) is a small‐molecule BCL-2 inhibitor that leads to the initiation of apoptosis.
In a phase 1b trial of venetoclax in combination with a hypomethylating agent, the overall CR rate was 35%, and the CRi rate was 35%.
“Again, higher than what would be expected with a hypomethylating agent alone,” Dr Altman said.
In a phase 1b/2 trial of venetoclax in combination with low‐dose cytarabine, the CR + CRi rate was 54%. Patients responded even if they had prior exposure to hypomethylating agents.
Mutation-specific novel agents
The FLT3 inhibitor midostaurin and the IDH inhibitors AG-120 and AG-221 are among the most exciting mutation-specific agents and the ones most progressed, according to Dr Altman.
FLT3-ITD is mutated in about 30% of AML patients and carries an unfavorable prognosis, and the IDH mutation occurs in about 10% and confers a favorable prognosis.
Midostaurin
A phase 3, randomized, double-blind study of daunorubicin/cytarabine induction and high-dose cytarabine consolidation with midostaurin (PKC412) or placebo had a 59% CR rate by day 60 in the midostaurin arm, compared with 53% in the placebo arm.
“The CR rate was slightly higher in the midostaurin arm,” Dr Altman said, “but what’s the most remarkable about this study is the difference in overall survival.”
The median OS in the midostaurin arm was 74.7 months, compared with 25.6 months in the placebo arm (P=0.0074).
“The major take-home message from this clinical trial,” Dr Altman said, “is that midostaurin improved the overall survival when added to standard therapy and represents a new standard of care.”
AG-120 and AG-221
Two IDH inhibitors that have substantial data available are the IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221.
As of October 2015, 78 patients had been treated with AG-120 in a phase 1 trial, yielding an overall response rate of 35% and a CR rate of 15%.
As of September 2015, 209 patients had been treated with AG-221 in a phase 1/2 trial, and 66 are still on study. The overall response rate was 37% in 159 adults with relapsed/refractory AML, with a median duration of response of 6.9 months. The CR rate was 18%.
Investigators have initiated a phase 3 study of AG-221 compared to conventional care regimens.
NEW YORK—We are “finally” making progress in the treatment of acute myeloid leukemia (AML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
Jessica K. Altman, MD, said a number of developments have resulted in improved AML treatment, including a better understanding of biology and prognostic assessment, continued advances in transplant, and updating standard treatments and incorporating novel agents in both relapsed/refractory and newly diagnosed patients.
“There are a couple of practice-changing treatments in acute myeloid leukemia, 2 of which happened over the last decade: daunorubicin intensification and the use of FLT3 inhibitors,” said Dr Altman, an associate professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Dr Altman went on to explain that novel therapies for AML can be divided into 2 basic categories. There are agents that don’t depend on mutation status (like daunorubicin) and those that are mutation-specific (like FLT3 inhibitors).
Therapies not dependent on mutational complexity
The therapies that are not dependent on mutational complexity include anti-CD33 antibodies, BCL‐2 inhibitors, a dose-intensified anthracycline regimen, and different formulations of 7+3, including CPX‐351.
Escalated daunorubicin
Randomized trials of escalated daunorubicin (90 vs 45 mg/m2) have demonstrated benefit in complete responses (CRs) and overall survival (OS) in intermediate-risk patients and patients with core-binding factor mutation. They have demonstrated benefit in OS in FLT3 ITD+ patients.
In patients up to 65 years of age, 60–90 mg/m2 of daunorubicin is now standard.
“It’s still not clear to me—and I don’t know if it ever will be—if 90 is equivalent to 60,” Dr Altman said.
CPX-351
CPX-351 is a liposomal formulation of cytarabine and daunorubicin. In a randomized, phase 3 study of older adults with secondary AML, the median OS was 9.56 months for patients treated with CPX-351 and 5.95 months for patients on the 7+3 regimen (P=0.005).
The median event-free survival was significantly better with CPX-351 (P=0.021), as was the rate of CR + CR with incomplete blood count recovery (CRi). The rate of CR + CRi was 47.7% with CPX-351 and 33.3% for 7+3 (P=0.016).
A similar number of patients went on to transplant in each arm. Grade 3-5 adverse events were similar in frequency and severity in both arms—92% with CPX-351 vs 91% with 7+3.
SGN-CD33A
CD33 is not a new target in myeloid leukemia, Dr Altman pointed out. Gemtuzumab ozogamicin has been studied, approved by the US Food and Drug Administration, and then withdrawn.
However, an increasing number of studies with gemtuzumab are underway, she said, and the agent may once again have a place in the AML armamentarium.
The newest CD33 construct is SGN-CD33A, a stable dipeptide linker that enables uniform drug loading of a pyrrolobenzodiazepine dimer that crosslinks DNA and leads to cell death.
“Single-agent data was quite promising,” Dr Altman noted, with a CR + CRi rate of 41% in previously treated patients and 58% in 12 treatment-naïve patients.
These results prompted a combination study of SGN-CD33A with hypomethylating agents.
“Results were higher than expected with a hypomethylating agent,” Dr Altman pointed out.
The CR + CRi + CR with incomplete platelet recovery was 58%. And the median relapse-free survival was 7.7 months.
A phase 3 randomized trial of SGN-CD33A is planned.
Venetoclax
BCL-2 inhibitors are the fourth type of agent not dependent on mutation complexity. Venetoclax (ABT‐199) is a small‐molecule BCL-2 inhibitor that leads to the initiation of apoptosis.
In a phase 1b trial of venetoclax in combination with a hypomethylating agent, the overall CR rate was 35%, and the CRi rate was 35%.
“Again, higher than what would be expected with a hypomethylating agent alone,” Dr Altman said.
In a phase 1b/2 trial of venetoclax in combination with low‐dose cytarabine, the CR + CRi rate was 54%. Patients responded even if they had prior exposure to hypomethylating agents.
Mutation-specific novel agents
The FLT3 inhibitor midostaurin and the IDH inhibitors AG-120 and AG-221 are among the most exciting mutation-specific agents and the ones most progressed, according to Dr Altman.
FLT3-ITD is mutated in about 30% of AML patients and carries an unfavorable prognosis, and the IDH mutation occurs in about 10% and confers a favorable prognosis.
Midostaurin
A phase 3, randomized, double-blind study of daunorubicin/cytarabine induction and high-dose cytarabine consolidation with midostaurin (PKC412) or placebo had a 59% CR rate by day 60 in the midostaurin arm, compared with 53% in the placebo arm.
“The CR rate was slightly higher in the midostaurin arm,” Dr Altman said, “but what’s the most remarkable about this study is the difference in overall survival.”
The median OS in the midostaurin arm was 74.7 months, compared with 25.6 months in the placebo arm (P=0.0074).
“The major take-home message from this clinical trial,” Dr Altman said, “is that midostaurin improved the overall survival when added to standard therapy and represents a new standard of care.”
AG-120 and AG-221
Two IDH inhibitors that have substantial data available are the IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221.
As of October 2015, 78 patients had been treated with AG-120 in a phase 1 trial, yielding an overall response rate of 35% and a CR rate of 15%.
As of September 2015, 209 patients had been treated with AG-221 in a phase 1/2 trial, and 66 are still on study. The overall response rate was 37% in 159 adults with relapsed/refractory AML, with a median duration of response of 6.9 months. The CR rate was 18%.
Investigators have initiated a phase 3 study of AG-221 compared to conventional care regimens.
NEW YORK—We are “finally” making progress in the treatment of acute myeloid leukemia (AML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
Jessica K. Altman, MD, said a number of developments have resulted in improved AML treatment, including a better understanding of biology and prognostic assessment, continued advances in transplant, and updating standard treatments and incorporating novel agents in both relapsed/refractory and newly diagnosed patients.
“There are a couple of practice-changing treatments in acute myeloid leukemia, 2 of which happened over the last decade: daunorubicin intensification and the use of FLT3 inhibitors,” said Dr Altman, an associate professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Dr Altman went on to explain that novel therapies for AML can be divided into 2 basic categories. There are agents that don’t depend on mutation status (like daunorubicin) and those that are mutation-specific (like FLT3 inhibitors).
Therapies not dependent on mutational complexity
The therapies that are not dependent on mutational complexity include anti-CD33 antibodies, BCL‐2 inhibitors, a dose-intensified anthracycline regimen, and different formulations of 7+3, including CPX‐351.
Escalated daunorubicin
Randomized trials of escalated daunorubicin (90 vs 45 mg/m2) have demonstrated benefit in complete responses (CRs) and overall survival (OS) in intermediate-risk patients and patients with core-binding factor mutation. They have demonstrated benefit in OS in FLT3 ITD+ patients.
In patients up to 65 years of age, 60–90 mg/m2 of daunorubicin is now standard.
“It’s still not clear to me—and I don’t know if it ever will be—if 90 is equivalent to 60,” Dr Altman said.
CPX-351
CPX-351 is a liposomal formulation of cytarabine and daunorubicin. In a randomized, phase 3 study of older adults with secondary AML, the median OS was 9.56 months for patients treated with CPX-351 and 5.95 months for patients on the 7+3 regimen (P=0.005).
The median event-free survival was significantly better with CPX-351 (P=0.021), as was the rate of CR + CR with incomplete blood count recovery (CRi). The rate of CR + CRi was 47.7% with CPX-351 and 33.3% for 7+3 (P=0.016).
A similar number of patients went on to transplant in each arm. Grade 3-5 adverse events were similar in frequency and severity in both arms—92% with CPX-351 vs 91% with 7+3.
SGN-CD33A
CD33 is not a new target in myeloid leukemia, Dr Altman pointed out. Gemtuzumab ozogamicin has been studied, approved by the US Food and Drug Administration, and then withdrawn.
However, an increasing number of studies with gemtuzumab are underway, she said, and the agent may once again have a place in the AML armamentarium.
The newest CD33 construct is SGN-CD33A, a stable dipeptide linker that enables uniform drug loading of a pyrrolobenzodiazepine dimer that crosslinks DNA and leads to cell death.
“Single-agent data was quite promising,” Dr Altman noted, with a CR + CRi rate of 41% in previously treated patients and 58% in 12 treatment-naïve patients.
These results prompted a combination study of SGN-CD33A with hypomethylating agents.
“Results were higher than expected with a hypomethylating agent,” Dr Altman pointed out.
The CR + CRi + CR with incomplete platelet recovery was 58%. And the median relapse-free survival was 7.7 months.
A phase 3 randomized trial of SGN-CD33A is planned.
Venetoclax
BCL-2 inhibitors are the fourth type of agent not dependent on mutation complexity. Venetoclax (ABT‐199) is a small‐molecule BCL-2 inhibitor that leads to the initiation of apoptosis.
In a phase 1b trial of venetoclax in combination with a hypomethylating agent, the overall CR rate was 35%, and the CRi rate was 35%.
“Again, higher than what would be expected with a hypomethylating agent alone,” Dr Altman said.
In a phase 1b/2 trial of venetoclax in combination with low‐dose cytarabine, the CR + CRi rate was 54%. Patients responded even if they had prior exposure to hypomethylating agents.
Mutation-specific novel agents
The FLT3 inhibitor midostaurin and the IDH inhibitors AG-120 and AG-221 are among the most exciting mutation-specific agents and the ones most progressed, according to Dr Altman.
FLT3-ITD is mutated in about 30% of AML patients and carries an unfavorable prognosis, and the IDH mutation occurs in about 10% and confers a favorable prognosis.
Midostaurin
A phase 3, randomized, double-blind study of daunorubicin/cytarabine induction and high-dose cytarabine consolidation with midostaurin (PKC412) or placebo had a 59% CR rate by day 60 in the midostaurin arm, compared with 53% in the placebo arm.
“The CR rate was slightly higher in the midostaurin arm,” Dr Altman said, “but what’s the most remarkable about this study is the difference in overall survival.”
The median OS in the midostaurin arm was 74.7 months, compared with 25.6 months in the placebo arm (P=0.0074).
“The major take-home message from this clinical trial,” Dr Altman said, “is that midostaurin improved the overall survival when added to standard therapy and represents a new standard of care.”
AG-120 and AG-221
Two IDH inhibitors that have substantial data available are the IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221.
As of October 2015, 78 patients had been treated with AG-120 in a phase 1 trial, yielding an overall response rate of 35% and a CR rate of 15%.
As of September 2015, 209 patients had been treated with AG-221 in a phase 1/2 trial, and 66 are still on study. The overall response rate was 37% in 159 adults with relapsed/refractory AML, with a median duration of response of 6.9 months. The CR rate was 18%.
Investigators have initiated a phase 3 study of AG-221 compared to conventional care regimens.
Doc offers advice on choosing a frontline TKI
Photo by D. Meyer
NEW YORK—Evaluating treatment goals is essential when choosing which tyrosine kinase inhibitor (TKI) to prescribe for a patient with newly diagnosed chronic myeloid leukemia (CML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
“Deciding what TKI to start people on really depends on what your goals are for that patient,” said the speaker, Jerald Radich, MD, of the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance in Seattle, Washington.
Because the 3 TKIs approved for frontline treatment of CML—imatinib, dasatinib, and nilotinib—produce “amazingly similar” responses, treatment compliance becomes an important factor in patient outcomes, he noted.
“If you take 90% of your imatinib, your MMR [major molecular response] is 90%,” he said. “Your CMR [complete molecular response] is 40%. So taking drug obviously trumps the decision of what drug to take.”
Dr Radich added that the major goal of treatment is to keep patients out of accelerated-phase blast crisis. Once people progress to blast crisis on a TKI, the median survival is less than 1 year.
“So that’s why you treat people aggressively, that’s why you monitor them molecularly, to prevent that from happening,” he said.
Treatment goals
Aside from preventing patients from progressing to blast crisis, treatment goals vary.
Achieving early molecular response (MR) impacts progression and survival, as does achieving a complete cytogenetic response (CCyR).
A major molecular response (MMR) is considered a “safe haven,” Dr Radich said, because once people achieve it, they almost never progress if they stay on drug.
And with a deep/complete molecular response (CMR), patients may potentially discontinue the drug.
So how your response goals line up determines how you use the agents for your treatment course, Dr Radich said.
In all response categories—patients with CCyR, MMR, MR, CMR—survival is virtually within 95% of survival for the general population.
“This is absolutely astonishing,” Dr Radich said.
He emphasized the importance of molecular testing at 3 months and achieving a BCR-ABL level of less than 10%.
Patients who have more than 10% blasts at 3 months have an 88% chance of achieving MMR at 4 years, while those who still have more than 10% blasts at 6 months have a 3.3% chance of achieving MMR at 4 years.
Toxicity
Side effects common to the 3 frontline TKIs are myelosuppression, transaminase elevation, and change in electrolytes. Dr Radich noted that imatinib doesn’t cause much myelosuppression.
“You can give imatinib on day 28 after allogeneic transplant, and it doesn’t affect the counts, which I think is pretty darn good proof that it doesn’t have any primary hematopoietic toxicity,” he said. “You can’t try that trick with the others.”
Venous and arterial cardiovascular events with TKIs are more recently coming to light.
Cardiovascular events with imatinib are about the same as the general population, Dr Radich said.
“[In] fact, some people think it might be protective,” he noted.
Discontinuation
“When we first started treating people with these drugs, we figured that they would be on them for life . . . ,” Dr Radich said. “[Y]ou’d always have a reservoir of CML cells because you can’t extinguish all the stem cells.”
A mathematical model predicted it would take 30 to 40 years to wipe out all CML cells with a TKI. The cumulative cure rate after 15 years of treatment would be 14%. After 30 years, it would be 31%.
Conducting a discontinuation trial would have been out of the question based on these predictions.
“Fortunately, some of the people who did the next trials hadn’t read that literature,” Dr Radich said.
One discontinuation trial (EURO-SKI) included patients who had been on drug for at least 3 years and had CMR for at least 1 year. About half stayed in PCR negativity, now up to 4 years.
A number of trials are now underway evaluating the possibility of TKI discontinuation, and they are showing that between 40% and 50% of patients can remain off drug for years.
Using generic imatinib
While generic imatinib is good for cost-effective, long-term use, second-generation TKIs are better at preventing accelerated-phase blast crisis, Dr Radich said.
The second generation is also better at producing deep remissions, and discontinuation could bring with it a cost savings.
Dr Radich calculated that it cost about $2.5 million for every patient who achieves treatment-free remission using a TKI, while transplant cost $1.31 million per patient who achieves treatment-free remission.
So generic imatinib is good for low- and intermediate-risk patients, as well as for older, sicker patients.
Second-generation TKIs are appropriate for higher-risk patients until they achieve a CCyR or MMR, then they can switch to generic imatinib.
And second-generation TKIs should be used for younger patients in whom drug discontinuation is important.
Frontline treatment observations
In summary, Dr Radich made the following observations about frontline treatment in CML.
- For overall survival, imatinib is equivalent to second-generation TKIs.
- To achieve a deep MR, a second-generation TKI is better than imatinib.
- Discontinuation is equally successful with all TKIs.
- For lower-risk CML, imatinib is equivalent to second-generation TKIs.
- When it comes to progression and possibly high-risk CML, second-generation TKIs are better than imatinib.
- Second-generation TKIs produce more long-term toxicities than imatinib.
- There is substantial cost savings with generics.
Photo by D. Meyer
NEW YORK—Evaluating treatment goals is essential when choosing which tyrosine kinase inhibitor (TKI) to prescribe for a patient with newly diagnosed chronic myeloid leukemia (CML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
“Deciding what TKI to start people on really depends on what your goals are for that patient,” said the speaker, Jerald Radich, MD, of the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance in Seattle, Washington.
Because the 3 TKIs approved for frontline treatment of CML—imatinib, dasatinib, and nilotinib—produce “amazingly similar” responses, treatment compliance becomes an important factor in patient outcomes, he noted.
“If you take 90% of your imatinib, your MMR [major molecular response] is 90%,” he said. “Your CMR [complete molecular response] is 40%. So taking drug obviously trumps the decision of what drug to take.”
Dr Radich added that the major goal of treatment is to keep patients out of accelerated-phase blast crisis. Once people progress to blast crisis on a TKI, the median survival is less than 1 year.
“So that’s why you treat people aggressively, that’s why you monitor them molecularly, to prevent that from happening,” he said.
Treatment goals
Aside from preventing patients from progressing to blast crisis, treatment goals vary.
Achieving early molecular response (MR) impacts progression and survival, as does achieving a complete cytogenetic response (CCyR).
A major molecular response (MMR) is considered a “safe haven,” Dr Radich said, because once people achieve it, they almost never progress if they stay on drug.
And with a deep/complete molecular response (CMR), patients may potentially discontinue the drug.
So how your response goals line up determines how you use the agents for your treatment course, Dr Radich said.
In all response categories—patients with CCyR, MMR, MR, CMR—survival is virtually within 95% of survival for the general population.
“This is absolutely astonishing,” Dr Radich said.
He emphasized the importance of molecular testing at 3 months and achieving a BCR-ABL level of less than 10%.
Patients who have more than 10% blasts at 3 months have an 88% chance of achieving MMR at 4 years, while those who still have more than 10% blasts at 6 months have a 3.3% chance of achieving MMR at 4 years.
Toxicity
Side effects common to the 3 frontline TKIs are myelosuppression, transaminase elevation, and change in electrolytes. Dr Radich noted that imatinib doesn’t cause much myelosuppression.
“You can give imatinib on day 28 after allogeneic transplant, and it doesn’t affect the counts, which I think is pretty darn good proof that it doesn’t have any primary hematopoietic toxicity,” he said. “You can’t try that trick with the others.”
Venous and arterial cardiovascular events with TKIs are more recently coming to light.
Cardiovascular events with imatinib are about the same as the general population, Dr Radich said.
“[In] fact, some people think it might be protective,” he noted.
Discontinuation
“When we first started treating people with these drugs, we figured that they would be on them for life . . . ,” Dr Radich said. “[Y]ou’d always have a reservoir of CML cells because you can’t extinguish all the stem cells.”
A mathematical model predicted it would take 30 to 40 years to wipe out all CML cells with a TKI. The cumulative cure rate after 15 years of treatment would be 14%. After 30 years, it would be 31%.
Conducting a discontinuation trial would have been out of the question based on these predictions.
“Fortunately, some of the people who did the next trials hadn’t read that literature,” Dr Radich said.
One discontinuation trial (EURO-SKI) included patients who had been on drug for at least 3 years and had CMR for at least 1 year. About half stayed in PCR negativity, now up to 4 years.
A number of trials are now underway evaluating the possibility of TKI discontinuation, and they are showing that between 40% and 50% of patients can remain off drug for years.
Using generic imatinib
While generic imatinib is good for cost-effective, long-term use, second-generation TKIs are better at preventing accelerated-phase blast crisis, Dr Radich said.
The second generation is also better at producing deep remissions, and discontinuation could bring with it a cost savings.
Dr Radich calculated that it cost about $2.5 million for every patient who achieves treatment-free remission using a TKI, while transplant cost $1.31 million per patient who achieves treatment-free remission.
So generic imatinib is good for low- and intermediate-risk patients, as well as for older, sicker patients.
Second-generation TKIs are appropriate for higher-risk patients until they achieve a CCyR or MMR, then they can switch to generic imatinib.
And second-generation TKIs should be used for younger patients in whom drug discontinuation is important.
Frontline treatment observations
In summary, Dr Radich made the following observations about frontline treatment in CML.
- For overall survival, imatinib is equivalent to second-generation TKIs.
- To achieve a deep MR, a second-generation TKI is better than imatinib.
- Discontinuation is equally successful with all TKIs.
- For lower-risk CML, imatinib is equivalent to second-generation TKIs.
- When it comes to progression and possibly high-risk CML, second-generation TKIs are better than imatinib.
- Second-generation TKIs produce more long-term toxicities than imatinib.
- There is substantial cost savings with generics.
Photo by D. Meyer
NEW YORK—Evaluating treatment goals is essential when choosing which tyrosine kinase inhibitor (TKI) to prescribe for a patient with newly diagnosed chronic myeloid leukemia (CML), according to a speaker at the NCCN 11th Annual Congress: Hematologic Malignancies.
“Deciding what TKI to start people on really depends on what your goals are for that patient,” said the speaker, Jerald Radich, MD, of the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance in Seattle, Washington.
Because the 3 TKIs approved for frontline treatment of CML—imatinib, dasatinib, and nilotinib—produce “amazingly similar” responses, treatment compliance becomes an important factor in patient outcomes, he noted.
“If you take 90% of your imatinib, your MMR [major molecular response] is 90%,” he said. “Your CMR [complete molecular response] is 40%. So taking drug obviously trumps the decision of what drug to take.”
Dr Radich added that the major goal of treatment is to keep patients out of accelerated-phase blast crisis. Once people progress to blast crisis on a TKI, the median survival is less than 1 year.
“So that’s why you treat people aggressively, that’s why you monitor them molecularly, to prevent that from happening,” he said.
Treatment goals
Aside from preventing patients from progressing to blast crisis, treatment goals vary.
Achieving early molecular response (MR) impacts progression and survival, as does achieving a complete cytogenetic response (CCyR).
A major molecular response (MMR) is considered a “safe haven,” Dr Radich said, because once people achieve it, they almost never progress if they stay on drug.
And with a deep/complete molecular response (CMR), patients may potentially discontinue the drug.
So how your response goals line up determines how you use the agents for your treatment course, Dr Radich said.
In all response categories—patients with CCyR, MMR, MR, CMR—survival is virtually within 95% of survival for the general population.
“This is absolutely astonishing,” Dr Radich said.
He emphasized the importance of molecular testing at 3 months and achieving a BCR-ABL level of less than 10%.
Patients who have more than 10% blasts at 3 months have an 88% chance of achieving MMR at 4 years, while those who still have more than 10% blasts at 6 months have a 3.3% chance of achieving MMR at 4 years.
Toxicity
Side effects common to the 3 frontline TKIs are myelosuppression, transaminase elevation, and change in electrolytes. Dr Radich noted that imatinib doesn’t cause much myelosuppression.
“You can give imatinib on day 28 after allogeneic transplant, and it doesn’t affect the counts, which I think is pretty darn good proof that it doesn’t have any primary hematopoietic toxicity,” he said. “You can’t try that trick with the others.”
Venous and arterial cardiovascular events with TKIs are more recently coming to light.
Cardiovascular events with imatinib are about the same as the general population, Dr Radich said.
“[In] fact, some people think it might be protective,” he noted.
Discontinuation
“When we first started treating people with these drugs, we figured that they would be on them for life . . . ,” Dr Radich said. “[Y]ou’d always have a reservoir of CML cells because you can’t extinguish all the stem cells.”
A mathematical model predicted it would take 30 to 40 years to wipe out all CML cells with a TKI. The cumulative cure rate after 15 years of treatment would be 14%. After 30 years, it would be 31%.
Conducting a discontinuation trial would have been out of the question based on these predictions.
“Fortunately, some of the people who did the next trials hadn’t read that literature,” Dr Radich said.
One discontinuation trial (EURO-SKI) included patients who had been on drug for at least 3 years and had CMR for at least 1 year. About half stayed in PCR negativity, now up to 4 years.
A number of trials are now underway evaluating the possibility of TKI discontinuation, and they are showing that between 40% and 50% of patients can remain off drug for years.
Using generic imatinib
While generic imatinib is good for cost-effective, long-term use, second-generation TKIs are better at preventing accelerated-phase blast crisis, Dr Radich said.
The second generation is also better at producing deep remissions, and discontinuation could bring with it a cost savings.
Dr Radich calculated that it cost about $2.5 million for every patient who achieves treatment-free remission using a TKI, while transplant cost $1.31 million per patient who achieves treatment-free remission.
So generic imatinib is good for low- and intermediate-risk patients, as well as for older, sicker patients.
Second-generation TKIs are appropriate for higher-risk patients until they achieve a CCyR or MMR, then they can switch to generic imatinib.
And second-generation TKIs should be used for younger patients in whom drug discontinuation is important.
Frontline treatment observations
In summary, Dr Radich made the following observations about frontline treatment in CML.
- For overall survival, imatinib is equivalent to second-generation TKIs.
- To achieve a deep MR, a second-generation TKI is better than imatinib.
- Discontinuation is equally successful with all TKIs.
- For lower-risk CML, imatinib is equivalent to second-generation TKIs.
- When it comes to progression and possibly high-risk CML, second-generation TKIs are better than imatinib.
- Second-generation TKIs produce more long-term toxicities than imatinib.
- There is substantial cost savings with generics.
Physician, know thy patient before recommending treatment
Hollywood, FLA. – Although patients and physicians should always be partners in medical decision making, guiding patients into making medically sound choices may involve a lot of listening and empathy, often followed by a little friendly persuasion, suggests an expert in health care decision making,
“Even when you get to a situation where the clinical practice guideline would point toward shared decision making, we’ve got to do shared decision making right or the guideline just doesn’t do the work for us. We clinicians have to know how to partner with our patients to make decisions when their values matter,” said Dr. Peter A Ubel, professor of business, public policy, and medicine at Duke University, Durham, N.H.
Dr. Ubel discussed how to understand and use patient preferences in cancer treatment decisions at the annual conference of the National Comprehensive Cancer Network.
In the case of early-stage prostate cancer, for example, treatment options include surveillance or active treatment with surgery or radiation, but the risk/benefit trade-offs require careful discussion.
“The different approaches have different pros and cons: If you get active treatment, there’s a pretty good chance you’ll experience incontinence or erectile dysfunction, whereas if you undergo surveillance you won’t experience those as side effects of the surveillance strategy, but you will live with a cancer inside your body, the accompanying anxiety, and wondering every 6 months whether it has advanced,” Dr. Ubel said.
“The question is how do we go figure out which treatment is best for which patient?” he added.
What doctors say not always what patients hear
To examine how decisions are made, Dr. Ubel and his colleagues conducted a study in which patients scheduled for biopsy for suspicion of prostate cancer were approached at the time of their clinic visits and asked to participate in a study about prostate cancer decision making. Patients were given a booklet aimed at the seventh-grade reading level describing prostate cancer and its treatment, and were asked, once they had finished, what course of therapy they might pursue if the diagnosis turned out to be positive, and why. They also were asked if it was important to them to maintain natural sexual function.
The encounter between the patients and their urologists at the time of diagnosis were audio recorded, so that investigators could see whether physicians recommend specific treatments and why.
“One of the things that really jumped out in this study was just how much language, how much explanation urologists use to help patients understand their diagnosis,” Dr. Ubel said.
In one encounter, the urologist explained to the patient that 3 out of 12 biopsy cores had less than 30% cancer involvement, suggesting moderately low-risk disease, but then went on to talk about Gleason scores, tumor grades and patterns, and risk categories.
“When a patient just finds out he has prostate cancer, it’s a tough time to put a whole bunch of information in front of him for him to absorb and make a decision,” Dr. Ubel said. Patients need time to absorb the shock of a cancer diagnosis first – even a diagnosis of an early, easily treated cancer – and information overload may actually reduce their ability to comprehend their choices or retain the information, he added. The urologist in this scenario is making a very earnest effort to tell the patient that he doesn’t have the kind of cancer that’s ever going to kill him, or that it is highly unlikely to cause any problems for the next 10-15 years, and there is ample time to decide how to treat it.
“But the doctor kind of forgets that the patient doesn’t speak medicalese, and the doctor feels like you really have to give them thorough informed consent, after all. So you need to inform the heck out of patients with all of the medical detail you believe is necessary to understand the decision, instead of the translation of the medical detail into terms the patient can understand,” he said.
An important part of shared decision making, therefore, is to make sure that patients can understand their alternatives, but not to overwhelm them with detail, because they may give up and ask the physician, “What do you think I should do?” which can introduce physician bias that may not always lead to the right choice for that patient.
“I actually morally don’t recommend that. I think instead we should give the right amount of information at the right time so they can actually get engaged in the choice,” Dr. Ubel said.
Discussion informs choices
The investigators looked at how prediagnosis education materials and discussions with urologists shaped patient decisions about treatment choice. Patients were called before their appointments to ensure that they had read the booklet, and then just before the appointment were asked which way they were leaning if the diagnosis turned out to be positive.
The investigators found that of 44 patients who expressed a preference for active surveillance before the appointment, 55% actually went on to receive active treatment. Among 119 patients with no expressed preference for surveillance or active therapy, 46% went on to treatment, and of 118 expressing previsit preference only for active surveillance, 54% went on to receive it.
“The leaning that they had before seeing the doctor had no influence on what treatment they got,” Dr. Ubel said. Instead, physicians’ recommendations had a strong influence on treatment choice. Recommendations are an essential part of the discussion, “but I don’t think we often do them well,” he said.
Ask patients to think out loud about what they have read or have been told, and ask them to repeat in their own words what they heard the doctor say, Dr. Ubel suggested. It’s incumbent on the physician to try to understand the patient’s preferences, and say something like, “I’m the expert on medical facts, but you’re the expert on you,” or “What sounds good and bad to you about that treatment alternative?”
Finally, physicians need to make recommendations based on patient preferences, he said.
For example, in one recorded encounter, the physician asked the patient, “Are you the kind of person where the idea of just watching your PSA is that unsettling to you?” When the patient replied “Yeah, I think I would be,” the physician was able to make an informed recommendation, saying “then I don’t think you’d be a good candidate for surveillance.”
“This doctor did not just make a recommendation; he tried to find out something about the patient first, and that’s critical to giving good advice,” Dr. Ubel said.
Hollywood, FLA. – Although patients and physicians should always be partners in medical decision making, guiding patients into making medically sound choices may involve a lot of listening and empathy, often followed by a little friendly persuasion, suggests an expert in health care decision making,
“Even when you get to a situation where the clinical practice guideline would point toward shared decision making, we’ve got to do shared decision making right or the guideline just doesn’t do the work for us. We clinicians have to know how to partner with our patients to make decisions when their values matter,” said Dr. Peter A Ubel, professor of business, public policy, and medicine at Duke University, Durham, N.H.
Dr. Ubel discussed how to understand and use patient preferences in cancer treatment decisions at the annual conference of the National Comprehensive Cancer Network.
In the case of early-stage prostate cancer, for example, treatment options include surveillance or active treatment with surgery or radiation, but the risk/benefit trade-offs require careful discussion.
“The different approaches have different pros and cons: If you get active treatment, there’s a pretty good chance you’ll experience incontinence or erectile dysfunction, whereas if you undergo surveillance you won’t experience those as side effects of the surveillance strategy, but you will live with a cancer inside your body, the accompanying anxiety, and wondering every 6 months whether it has advanced,” Dr. Ubel said.
“The question is how do we go figure out which treatment is best for which patient?” he added.
What doctors say not always what patients hear
To examine how decisions are made, Dr. Ubel and his colleagues conducted a study in which patients scheduled for biopsy for suspicion of prostate cancer were approached at the time of their clinic visits and asked to participate in a study about prostate cancer decision making. Patients were given a booklet aimed at the seventh-grade reading level describing prostate cancer and its treatment, and were asked, once they had finished, what course of therapy they might pursue if the diagnosis turned out to be positive, and why. They also were asked if it was important to them to maintain natural sexual function.
The encounter between the patients and their urologists at the time of diagnosis were audio recorded, so that investigators could see whether physicians recommend specific treatments and why.
“One of the things that really jumped out in this study was just how much language, how much explanation urologists use to help patients understand their diagnosis,” Dr. Ubel said.
In one encounter, the urologist explained to the patient that 3 out of 12 biopsy cores had less than 30% cancer involvement, suggesting moderately low-risk disease, but then went on to talk about Gleason scores, tumor grades and patterns, and risk categories.
“When a patient just finds out he has prostate cancer, it’s a tough time to put a whole bunch of information in front of him for him to absorb and make a decision,” Dr. Ubel said. Patients need time to absorb the shock of a cancer diagnosis first – even a diagnosis of an early, easily treated cancer – and information overload may actually reduce their ability to comprehend their choices or retain the information, he added. The urologist in this scenario is making a very earnest effort to tell the patient that he doesn’t have the kind of cancer that’s ever going to kill him, or that it is highly unlikely to cause any problems for the next 10-15 years, and there is ample time to decide how to treat it.
“But the doctor kind of forgets that the patient doesn’t speak medicalese, and the doctor feels like you really have to give them thorough informed consent, after all. So you need to inform the heck out of patients with all of the medical detail you believe is necessary to understand the decision, instead of the translation of the medical detail into terms the patient can understand,” he said.
An important part of shared decision making, therefore, is to make sure that patients can understand their alternatives, but not to overwhelm them with detail, because they may give up and ask the physician, “What do you think I should do?” which can introduce physician bias that may not always lead to the right choice for that patient.
“I actually morally don’t recommend that. I think instead we should give the right amount of information at the right time so they can actually get engaged in the choice,” Dr. Ubel said.
Discussion informs choices
The investigators looked at how prediagnosis education materials and discussions with urologists shaped patient decisions about treatment choice. Patients were called before their appointments to ensure that they had read the booklet, and then just before the appointment were asked which way they were leaning if the diagnosis turned out to be positive.
The investigators found that of 44 patients who expressed a preference for active surveillance before the appointment, 55% actually went on to receive active treatment. Among 119 patients with no expressed preference for surveillance or active therapy, 46% went on to treatment, and of 118 expressing previsit preference only for active surveillance, 54% went on to receive it.
“The leaning that they had before seeing the doctor had no influence on what treatment they got,” Dr. Ubel said. Instead, physicians’ recommendations had a strong influence on treatment choice. Recommendations are an essential part of the discussion, “but I don’t think we often do them well,” he said.
Ask patients to think out loud about what they have read or have been told, and ask them to repeat in their own words what they heard the doctor say, Dr. Ubel suggested. It’s incumbent on the physician to try to understand the patient’s preferences, and say something like, “I’m the expert on medical facts, but you’re the expert on you,” or “What sounds good and bad to you about that treatment alternative?”
Finally, physicians need to make recommendations based on patient preferences, he said.
For example, in one recorded encounter, the physician asked the patient, “Are you the kind of person where the idea of just watching your PSA is that unsettling to you?” When the patient replied “Yeah, I think I would be,” the physician was able to make an informed recommendation, saying “then I don’t think you’d be a good candidate for surveillance.”
“This doctor did not just make a recommendation; he tried to find out something about the patient first, and that’s critical to giving good advice,” Dr. Ubel said.
Hollywood, FLA. – Although patients and physicians should always be partners in medical decision making, guiding patients into making medically sound choices may involve a lot of listening and empathy, often followed by a little friendly persuasion, suggests an expert in health care decision making,
“Even when you get to a situation where the clinical practice guideline would point toward shared decision making, we’ve got to do shared decision making right or the guideline just doesn’t do the work for us. We clinicians have to know how to partner with our patients to make decisions when their values matter,” said Dr. Peter A Ubel, professor of business, public policy, and medicine at Duke University, Durham, N.H.
Dr. Ubel discussed how to understand and use patient preferences in cancer treatment decisions at the annual conference of the National Comprehensive Cancer Network.
In the case of early-stage prostate cancer, for example, treatment options include surveillance or active treatment with surgery or radiation, but the risk/benefit trade-offs require careful discussion.
“The different approaches have different pros and cons: If you get active treatment, there’s a pretty good chance you’ll experience incontinence or erectile dysfunction, whereas if you undergo surveillance you won’t experience those as side effects of the surveillance strategy, but you will live with a cancer inside your body, the accompanying anxiety, and wondering every 6 months whether it has advanced,” Dr. Ubel said.
“The question is how do we go figure out which treatment is best for which patient?” he added.
What doctors say not always what patients hear
To examine how decisions are made, Dr. Ubel and his colleagues conducted a study in which patients scheduled for biopsy for suspicion of prostate cancer were approached at the time of their clinic visits and asked to participate in a study about prostate cancer decision making. Patients were given a booklet aimed at the seventh-grade reading level describing prostate cancer and its treatment, and were asked, once they had finished, what course of therapy they might pursue if the diagnosis turned out to be positive, and why. They also were asked if it was important to them to maintain natural sexual function.
The encounter between the patients and their urologists at the time of diagnosis were audio recorded, so that investigators could see whether physicians recommend specific treatments and why.
“One of the things that really jumped out in this study was just how much language, how much explanation urologists use to help patients understand their diagnosis,” Dr. Ubel said.
In one encounter, the urologist explained to the patient that 3 out of 12 biopsy cores had less than 30% cancer involvement, suggesting moderately low-risk disease, but then went on to talk about Gleason scores, tumor grades and patterns, and risk categories.
“When a patient just finds out he has prostate cancer, it’s a tough time to put a whole bunch of information in front of him for him to absorb and make a decision,” Dr. Ubel said. Patients need time to absorb the shock of a cancer diagnosis first – even a diagnosis of an early, easily treated cancer – and information overload may actually reduce their ability to comprehend their choices or retain the information, he added. The urologist in this scenario is making a very earnest effort to tell the patient that he doesn’t have the kind of cancer that’s ever going to kill him, or that it is highly unlikely to cause any problems for the next 10-15 years, and there is ample time to decide how to treat it.
“But the doctor kind of forgets that the patient doesn’t speak medicalese, and the doctor feels like you really have to give them thorough informed consent, after all. So you need to inform the heck out of patients with all of the medical detail you believe is necessary to understand the decision, instead of the translation of the medical detail into terms the patient can understand,” he said.
An important part of shared decision making, therefore, is to make sure that patients can understand their alternatives, but not to overwhelm them with detail, because they may give up and ask the physician, “What do you think I should do?” which can introduce physician bias that may not always lead to the right choice for that patient.
“I actually morally don’t recommend that. I think instead we should give the right amount of information at the right time so they can actually get engaged in the choice,” Dr. Ubel said.
Discussion informs choices
The investigators looked at how prediagnosis education materials and discussions with urologists shaped patient decisions about treatment choice. Patients were called before their appointments to ensure that they had read the booklet, and then just before the appointment were asked which way they were leaning if the diagnosis turned out to be positive.
The investigators found that of 44 patients who expressed a preference for active surveillance before the appointment, 55% actually went on to receive active treatment. Among 119 patients with no expressed preference for surveillance or active therapy, 46% went on to treatment, and of 118 expressing previsit preference only for active surveillance, 54% went on to receive it.
“The leaning that they had before seeing the doctor had no influence on what treatment they got,” Dr. Ubel said. Instead, physicians’ recommendations had a strong influence on treatment choice. Recommendations are an essential part of the discussion, “but I don’t think we often do them well,” he said.
Ask patients to think out loud about what they have read or have been told, and ask them to repeat in their own words what they heard the doctor say, Dr. Ubel suggested. It’s incumbent on the physician to try to understand the patient’s preferences, and say something like, “I’m the expert on medical facts, but you’re the expert on you,” or “What sounds good and bad to you about that treatment alternative?”
Finally, physicians need to make recommendations based on patient preferences, he said.
For example, in one recorded encounter, the physician asked the patient, “Are you the kind of person where the idea of just watching your PSA is that unsettling to you?” When the patient replied “Yeah, I think I would be,” the physician was able to make an informed recommendation, saying “then I don’t think you’d be a good candidate for surveillance.”
“This doctor did not just make a recommendation; he tried to find out something about the patient first, and that’s critical to giving good advice,” Dr. Ubel said.
AT THE NCCN ANNUAL CONFERENCE
Key clinical point: Clinicians should understand patients’ coping styles and personalities before making recommendations about comparable treatment options.
Major finding: Physician recommendations were the strongest determining factor in patient choices of prostate cancer therapies.
Data source: Study of 281 prostate cancer patients and their treatment-decision encounters with urologists.
Disclosures: Dr. Ubel reported having no relevant disclosures.
Prostate cancer’s future seen in molecular tests
HOLLYWOOD, FLA. – Current evidence suggests that molecular tests for prostate cancer are prognostic and can help clinicians and patients with difficult treatment decisions. In the not-too-distant future, gene tests could also guide choice of therapies.
“I think that the largest impact is going to come in areas of both the greatest treatment uncertainty and areas where we can be predictive about the response to treatment,” said Dr. Ashley Ross, a urologic oncologist and pathologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore.
Multigene panels may soon be able help identify which patients might benefit more from radical prostatectomy or radiation therapy, whether radiation therapy effects could be enhanced with the addition of androgen-deprivation therapy, and whether early use of docetaxel might add therapeutic benefit, he said at the annual conference of the National Comprehensive Cancer Network.
The 2016 iteration of the NCCN guidelines for the treatment of prostate cancer include a note stating that “men with clinically localized disease may consider the use of tumor-based molecular assays. Retrospective case cohort studies have shown that molecular assays performed on biopsy or prostatectomy specimens provide prognostic information independent of NCCN risk groups.”
The use of molecular assays may inform treatment decisions by helping to predict the likelihood of death if a patient is managed conservatively, risks for biochemical progression after radical prostatectomy or external beam therapy, and the likelihood that a patient could develop metastatic disease after radical prostatectomy or salvage radiotherapy, the guidelines say.
Dr. Ross reviewed the molecular biology of localized prostate cancer and the benefits and risks of currently available molecular tests.
“We’ve had an increased ability to get molecular information or genomic information from very limited amounts of routinely-stored pathologic tissue, and that’s resulted in the generation of many molecular-based tissue tests in prostate cancer. With the emergence of those tests and a lot of aggressive marketing, there has been a lot of confusion for patients and providers about whether we should use them or not and in what context,” he said.
Prostate cancer is genomically complex, even in the localized stage, with copy number alterations, deletions, and amplifications; chromosomal rearrangements; and point mutations, he said.
One of the best characterized genomic events is the early loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog). This gene works within the PI3 kinase (PI3K)/AKT pathway. PI3K pathway mutations have been identified in up to 40% of all primary prostate cancers and 100% of mutations, Dr. Ross explained.
Loss of PTEN itself has been detected in about 15%-40% of primary prostate cancers and 50% of metastases, and the loss correlates with disease stage and tumor grade.
The NCCN guidelines list six available tissue-based tests for prostate cancer prognosis, including tests based on general cancer features such as cell-cycle proliferation, and those based on specific molecular features of cancer.
An example of the general type of test is the Ki-67 immunohistochemistry (IHC) test, which looks for a cellular marker of proliferation, and has been shown to have independent prognostic significance after radiation therapy or radical prostatectomy. This test is not currently recommended by the Medicare Molecular Diagnostic Services (MolDx) program, however.
Another general-type test is the Polaris quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) panel, which tests for 31 cell-cycle-related genes and 15 “housekeeping” controls. This test is recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy. It has been shown to independently predict prostate cancer–specific mortality, biochemical failure/recurrence, and metastasis, the guidelines say.
Tests based on molecular features include:
• PTEN/ERG, an IHC or fluorescent in situ hybridization test that has been shown to predict prostate cancer–specific mortality, upgrading to Gleason pattern 4 on radical prostatectomy, and biochemical recurrence (not MolDx recommended).
• Decipher, a whole-transcriptome 1.4M RNA expression oligonucleotide microarray shown to predict biochemical failure, metastasis, and prostate cancer–specific mortality (recommended for postradical prostatectomy for patients with pT2 tumors with positive margins, and pT3 disease, and rising PSA above nadir);
• Oncotype DX, an RT-PCR assay for 12 prostate cancer genes and five housekeeping controls (recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy).
• ProMark, multiplex immunofluorescent staining of eight proteins, which has been shown to independently predict non–organ-confined pT3 disease or Gleason pattern 4 disease on radical prostatectomy (not reviewed).
Dr. Ross said that in his practice, he generally does not order molecular testing for surveillance of men older than 65 who have very-low-risk disease. For men with low-risk disease, however, molecular testing may help in clinical decision making to predict upgrading or disease progression.
“There’s limited data from surveillance populations, but these tests can be used in this context with retrospective data available, realizing that in most cases the tests will be confirmative, or another way of thinking about it is ‘noninformative,’ so there are some considerations about cost in that context,” he said. For men with intermediate or high-risk disease, however, currently available tests are not good at predicting what an individual patient’s response would be to a specific type of therapy, whether surgery, radiation, androgen deprivation, chemotherapy, or a combination.
“This is an area where predictive biomarkers would be very informative. There is ongoing research, and I think this is an area of potentially large advancement in how we risk-stratify our patients,” Dr. Ross said.
HOLLYWOOD, FLA. – Current evidence suggests that molecular tests for prostate cancer are prognostic and can help clinicians and patients with difficult treatment decisions. In the not-too-distant future, gene tests could also guide choice of therapies.
“I think that the largest impact is going to come in areas of both the greatest treatment uncertainty and areas where we can be predictive about the response to treatment,” said Dr. Ashley Ross, a urologic oncologist and pathologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore.
Multigene panels may soon be able help identify which patients might benefit more from radical prostatectomy or radiation therapy, whether radiation therapy effects could be enhanced with the addition of androgen-deprivation therapy, and whether early use of docetaxel might add therapeutic benefit, he said at the annual conference of the National Comprehensive Cancer Network.
The 2016 iteration of the NCCN guidelines for the treatment of prostate cancer include a note stating that “men with clinically localized disease may consider the use of tumor-based molecular assays. Retrospective case cohort studies have shown that molecular assays performed on biopsy or prostatectomy specimens provide prognostic information independent of NCCN risk groups.”
The use of molecular assays may inform treatment decisions by helping to predict the likelihood of death if a patient is managed conservatively, risks for biochemical progression after radical prostatectomy or external beam therapy, and the likelihood that a patient could develop metastatic disease after radical prostatectomy or salvage radiotherapy, the guidelines say.
Dr. Ross reviewed the molecular biology of localized prostate cancer and the benefits and risks of currently available molecular tests.
“We’ve had an increased ability to get molecular information or genomic information from very limited amounts of routinely-stored pathologic tissue, and that’s resulted in the generation of many molecular-based tissue tests in prostate cancer. With the emergence of those tests and a lot of aggressive marketing, there has been a lot of confusion for patients and providers about whether we should use them or not and in what context,” he said.
Prostate cancer is genomically complex, even in the localized stage, with copy number alterations, deletions, and amplifications; chromosomal rearrangements; and point mutations, he said.
One of the best characterized genomic events is the early loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog). This gene works within the PI3 kinase (PI3K)/AKT pathway. PI3K pathway mutations have been identified in up to 40% of all primary prostate cancers and 100% of mutations, Dr. Ross explained.
Loss of PTEN itself has been detected in about 15%-40% of primary prostate cancers and 50% of metastases, and the loss correlates with disease stage and tumor grade.
The NCCN guidelines list six available tissue-based tests for prostate cancer prognosis, including tests based on general cancer features such as cell-cycle proliferation, and those based on specific molecular features of cancer.
An example of the general type of test is the Ki-67 immunohistochemistry (IHC) test, which looks for a cellular marker of proliferation, and has been shown to have independent prognostic significance after radiation therapy or radical prostatectomy. This test is not currently recommended by the Medicare Molecular Diagnostic Services (MolDx) program, however.
Another general-type test is the Polaris quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) panel, which tests for 31 cell-cycle-related genes and 15 “housekeeping” controls. This test is recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy. It has been shown to independently predict prostate cancer–specific mortality, biochemical failure/recurrence, and metastasis, the guidelines say.
Tests based on molecular features include:
• PTEN/ERG, an IHC or fluorescent in situ hybridization test that has been shown to predict prostate cancer–specific mortality, upgrading to Gleason pattern 4 on radical prostatectomy, and biochemical recurrence (not MolDx recommended).
• Decipher, a whole-transcriptome 1.4M RNA expression oligonucleotide microarray shown to predict biochemical failure, metastasis, and prostate cancer–specific mortality (recommended for postradical prostatectomy for patients with pT2 tumors with positive margins, and pT3 disease, and rising PSA above nadir);
• Oncotype DX, an RT-PCR assay for 12 prostate cancer genes and five housekeeping controls (recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy).
• ProMark, multiplex immunofluorescent staining of eight proteins, which has been shown to independently predict non–organ-confined pT3 disease or Gleason pattern 4 disease on radical prostatectomy (not reviewed).
Dr. Ross said that in his practice, he generally does not order molecular testing for surveillance of men older than 65 who have very-low-risk disease. For men with low-risk disease, however, molecular testing may help in clinical decision making to predict upgrading or disease progression.
“There’s limited data from surveillance populations, but these tests can be used in this context with retrospective data available, realizing that in most cases the tests will be confirmative, or another way of thinking about it is ‘noninformative,’ so there are some considerations about cost in that context,” he said. For men with intermediate or high-risk disease, however, currently available tests are not good at predicting what an individual patient’s response would be to a specific type of therapy, whether surgery, radiation, androgen deprivation, chemotherapy, or a combination.
“This is an area where predictive biomarkers would be very informative. There is ongoing research, and I think this is an area of potentially large advancement in how we risk-stratify our patients,” Dr. Ross said.
HOLLYWOOD, FLA. – Current evidence suggests that molecular tests for prostate cancer are prognostic and can help clinicians and patients with difficult treatment decisions. In the not-too-distant future, gene tests could also guide choice of therapies.
“I think that the largest impact is going to come in areas of both the greatest treatment uncertainty and areas where we can be predictive about the response to treatment,” said Dr. Ashley Ross, a urologic oncologist and pathologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore.
Multigene panels may soon be able help identify which patients might benefit more from radical prostatectomy or radiation therapy, whether radiation therapy effects could be enhanced with the addition of androgen-deprivation therapy, and whether early use of docetaxel might add therapeutic benefit, he said at the annual conference of the National Comprehensive Cancer Network.
The 2016 iteration of the NCCN guidelines for the treatment of prostate cancer include a note stating that “men with clinically localized disease may consider the use of tumor-based molecular assays. Retrospective case cohort studies have shown that molecular assays performed on biopsy or prostatectomy specimens provide prognostic information independent of NCCN risk groups.”
The use of molecular assays may inform treatment decisions by helping to predict the likelihood of death if a patient is managed conservatively, risks for biochemical progression after radical prostatectomy or external beam therapy, and the likelihood that a patient could develop metastatic disease after radical prostatectomy or salvage radiotherapy, the guidelines say.
Dr. Ross reviewed the molecular biology of localized prostate cancer and the benefits and risks of currently available molecular tests.
“We’ve had an increased ability to get molecular information or genomic information from very limited amounts of routinely-stored pathologic tissue, and that’s resulted in the generation of many molecular-based tissue tests in prostate cancer. With the emergence of those tests and a lot of aggressive marketing, there has been a lot of confusion for patients and providers about whether we should use them or not and in what context,” he said.
Prostate cancer is genomically complex, even in the localized stage, with copy number alterations, deletions, and amplifications; chromosomal rearrangements; and point mutations, he said.
One of the best characterized genomic events is the early loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog). This gene works within the PI3 kinase (PI3K)/AKT pathway. PI3K pathway mutations have been identified in up to 40% of all primary prostate cancers and 100% of mutations, Dr. Ross explained.
Loss of PTEN itself has been detected in about 15%-40% of primary prostate cancers and 50% of metastases, and the loss correlates with disease stage and tumor grade.
The NCCN guidelines list six available tissue-based tests for prostate cancer prognosis, including tests based on general cancer features such as cell-cycle proliferation, and those based on specific molecular features of cancer.
An example of the general type of test is the Ki-67 immunohistochemistry (IHC) test, which looks for a cellular marker of proliferation, and has been shown to have independent prognostic significance after radiation therapy or radical prostatectomy. This test is not currently recommended by the Medicare Molecular Diagnostic Services (MolDx) program, however.
Another general-type test is the Polaris quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) panel, which tests for 31 cell-cycle-related genes and 15 “housekeeping” controls. This test is recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy. It has been shown to independently predict prostate cancer–specific mortality, biochemical failure/recurrence, and metastasis, the guidelines say.
Tests based on molecular features include:
• PTEN/ERG, an IHC or fluorescent in situ hybridization test that has been shown to predict prostate cancer–specific mortality, upgrading to Gleason pattern 4 on radical prostatectomy, and biochemical recurrence (not MolDx recommended).
• Decipher, a whole-transcriptome 1.4M RNA expression oligonucleotide microarray shown to predict biochemical failure, metastasis, and prostate cancer–specific mortality (recommended for postradical prostatectomy for patients with pT2 tumors with positive margins, and pT3 disease, and rising PSA above nadir);
• Oncotype DX, an RT-PCR assay for 12 prostate cancer genes and five housekeeping controls (recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy).
• ProMark, multiplex immunofluorescent staining of eight proteins, which has been shown to independently predict non–organ-confined pT3 disease or Gleason pattern 4 disease on radical prostatectomy (not reviewed).
Dr. Ross said that in his practice, he generally does not order molecular testing for surveillance of men older than 65 who have very-low-risk disease. For men with low-risk disease, however, molecular testing may help in clinical decision making to predict upgrading or disease progression.
“There’s limited data from surveillance populations, but these tests can be used in this context with retrospective data available, realizing that in most cases the tests will be confirmative, or another way of thinking about it is ‘noninformative,’ so there are some considerations about cost in that context,” he said. For men with intermediate or high-risk disease, however, currently available tests are not good at predicting what an individual patient’s response would be to a specific type of therapy, whether surgery, radiation, androgen deprivation, chemotherapy, or a combination.
“This is an area where predictive biomarkers would be very informative. There is ongoing research, and I think this is an area of potentially large advancement in how we risk-stratify our patients,” Dr. Ross said.
EXPERT ANALYSIS FROM THE NCCN ANNUAL CONFERENCE
Prostate cancer’s future seen in molecular tests
HOLLYWOOD, FLA. – Current evidence suggests that molecular tests for prostate cancer are prognostic and can help clinicians and patients with difficult treatment decisions. In the not-too-distant future, gene tests could also guide choice of therapies.
“I think that the largest impact is going to come in areas of both the greatest treatment uncertainty and areas where we can be predictive about the response to treatment,” said Dr. Ashley Ross, a urologic oncologist and pathologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore.
Multigene panels may soon be able help identify which patients might benefit more from radical prostatectomy or radiation therapy, whether radiation therapy effects could be enhanced with the addition of androgen-deprivation therapy, and whether early use of docetaxel might add therapeutic benefit, he said at the annual conference of the National Comprehensive Cancer Network.
The 2016 iteration of the NCCN guidelines for the treatment of prostate cancer include a note stating that “men with clinically localized disease may consider the use of tumor-based molecular assays. Retrospective case cohort studies have shown that molecular assays performed on biopsy or prostatectomy specimens provide prognostic information independent of NCCN risk groups.”
The use of molecular assays may inform treatment decisions by helping to predict the likelihood of death if a patient is managed conservatively, risks for biochemical progression after radical prostatectomy or external beam therapy, and the likelihood that a patient could develop metastatic disease after radical prostatectomy or salvage radiotherapy, the guidelines say.
Dr. Ross reviewed the molecular biology of localized prostate cancer and the benefits and risks of currently available molecular tests.
“We’ve had an increased ability to get molecular information or genomic information from very limited amounts of routinely-stored pathologic tissue, and that’s resulted in the generation of many molecular-based tissue tests in prostate cancer. With the emergence of those tests and a lot of aggressive marketing, there has been a lot of confusion for patients and providers about whether we should use them or not and in what context,” he said.
Prostate cancer is genomically complex, even in the localized stage, with copy number alterations, deletions, and amplifications; chromosomal rearrangements; and point mutations, he said.
One of the best characterized genomic events is the early loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog). This gene works within the PI3 kinase (PI3K)/AKT pathway. PI3K pathway mutations have been identified in up to 40% of all primary prostate cancers and 100% of mutations, Dr. Ross explained.
Loss of PTEN itself has been detected in about 15%-40% of primary prostate cancers and 50% of metastases, and the loss correlates with disease stage and tumor grade.
The NCCN guidelines list six available tissue-based tests for prostate cancer prognosis, including tests based on general cancer features such as cell-cycle proliferation, and those based on specific molecular features of cancer.
An example of the general type of test is the Ki-67 immunohistochemistry (IHC) test, which looks for a cellular marker of proliferation, and has been shown to have independent prognostic significance after radiation therapy or radical prostatectomy. This test is not currently recommended by the Medicare Molecular Diagnostic Services (MolDx) program, however.
Another general-type test is the Polaris quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) panel, which tests for 31 cell-cycle-related genes and 15 “housekeeping” controls. This test is recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy. It has been shown to independently predict prostate cancer–specific mortality, biochemical failure/recurrence, and metastasis, the guidelines say.
Tests based on molecular features include:
• PTEN/ERG, an IHC or fluorescent in situ hybridization test that has been shown to predict prostate cancer–specific mortality, upgrading to Gleason pattern 4 on radical prostatectomy, and biochemical recurrence (not MolDx recommended).
• Decipher, a whole-transcriptome 1.4M RNA expression oligonucleotide microarray shown to predict biochemical failure, metastasis, and prostate cancer–specific mortality (recommended for postradical prostatectomy for patients with pT2 tumors with positive margins, and pT3 disease, and rising PSA above nadir);
• Oncotype DX, an RT-PCR assay for 12 prostate cancer genes and five housekeeping controls (recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy).
• ProMark, multiplex immunofluorescent staining of eight proteins, which has been shown to independently predict non–organ-confined pT3 disease or Gleason pattern 4 disease on radical prostatectomy (not reviewed).
Dr. Ross said that in his practice, he generally does not order molecular testing for surveillance of men older than 65 who have very-low-risk disease. For men with low-risk disease, however, molecular testing may help in clinical decision making to predict upgrading or disease progression.
“There’s limited data from surveillance populations, but these tests can be used in this context with retrospective data available, realizing that in most cases the tests will be confirmative, or another way of thinking about it is ‘noninformative,’ so there are some considerations about cost in that context,” he said. For men with intermediate or high-risk disease, however, currently available tests are not good at predicting what an individual patient’s response would be to a specific type of therapy, whether surgery, radiation, androgen deprivation, chemotherapy, or a combination.
“This is an area where predictive biomarkers would be very informative. There is ongoing research, and I think this is an area of potentially large advancement in how we risk-stratify our patients,” Dr. Ross said.
HOLLYWOOD, FLA. – Current evidence suggests that molecular tests for prostate cancer are prognostic and can help clinicians and patients with difficult treatment decisions. In the not-too-distant future, gene tests could also guide choice of therapies.
“I think that the largest impact is going to come in areas of both the greatest treatment uncertainty and areas where we can be predictive about the response to treatment,” said Dr. Ashley Ross, a urologic oncologist and pathologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore.
Multigene panels may soon be able help identify which patients might benefit more from radical prostatectomy or radiation therapy, whether radiation therapy effects could be enhanced with the addition of androgen-deprivation therapy, and whether early use of docetaxel might add therapeutic benefit, he said at the annual conference of the National Comprehensive Cancer Network.
The 2016 iteration of the NCCN guidelines for the treatment of prostate cancer include a note stating that “men with clinically localized disease may consider the use of tumor-based molecular assays. Retrospective case cohort studies have shown that molecular assays performed on biopsy or prostatectomy specimens provide prognostic information independent of NCCN risk groups.”
The use of molecular assays may inform treatment decisions by helping to predict the likelihood of death if a patient is managed conservatively, risks for biochemical progression after radical prostatectomy or external beam therapy, and the likelihood that a patient could develop metastatic disease after radical prostatectomy or salvage radiotherapy, the guidelines say.
Dr. Ross reviewed the molecular biology of localized prostate cancer and the benefits and risks of currently available molecular tests.
“We’ve had an increased ability to get molecular information or genomic information from very limited amounts of routinely-stored pathologic tissue, and that’s resulted in the generation of many molecular-based tissue tests in prostate cancer. With the emergence of those tests and a lot of aggressive marketing, there has been a lot of confusion for patients and providers about whether we should use them or not and in what context,” he said.
Prostate cancer is genomically complex, even in the localized stage, with copy number alterations, deletions, and amplifications; chromosomal rearrangements; and point mutations, he said.
One of the best characterized genomic events is the early loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog). This gene works within the PI3 kinase (PI3K)/AKT pathway. PI3K pathway mutations have been identified in up to 40% of all primary prostate cancers and 100% of mutations, Dr. Ross explained.
Loss of PTEN itself has been detected in about 15%-40% of primary prostate cancers and 50% of metastases, and the loss correlates with disease stage and tumor grade.
The NCCN guidelines list six available tissue-based tests for prostate cancer prognosis, including tests based on general cancer features such as cell-cycle proliferation, and those based on specific molecular features of cancer.
An example of the general type of test is the Ki-67 immunohistochemistry (IHC) test, which looks for a cellular marker of proliferation, and has been shown to have independent prognostic significance after radiation therapy or radical prostatectomy. This test is not currently recommended by the Medicare Molecular Diagnostic Services (MolDx) program, however.
Another general-type test is the Polaris quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) panel, which tests for 31 cell-cycle-related genes and 15 “housekeeping” controls. This test is recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy. It has been shown to independently predict prostate cancer–specific mortality, biochemical failure/recurrence, and metastasis, the guidelines say.
Tests based on molecular features include:
• PTEN/ERG, an IHC or fluorescent in situ hybridization test that has been shown to predict prostate cancer–specific mortality, upgrading to Gleason pattern 4 on radical prostatectomy, and biochemical recurrence (not MolDx recommended).
• Decipher, a whole-transcriptome 1.4M RNA expression oligonucleotide microarray shown to predict biochemical failure, metastasis, and prostate cancer–specific mortality (recommended for postradical prostatectomy for patients with pT2 tumors with positive margins, and pT3 disease, and rising PSA above nadir);
• Oncotype DX, an RT-PCR assay for 12 prostate cancer genes and five housekeeping controls (recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy).
• ProMark, multiplex immunofluorescent staining of eight proteins, which has been shown to independently predict non–organ-confined pT3 disease or Gleason pattern 4 disease on radical prostatectomy (not reviewed).
Dr. Ross said that in his practice, he generally does not order molecular testing for surveillance of men older than 65 who have very-low-risk disease. For men with low-risk disease, however, molecular testing may help in clinical decision making to predict upgrading or disease progression.
“There’s limited data from surveillance populations, but these tests can be used in this context with retrospective data available, realizing that in most cases the tests will be confirmative, or another way of thinking about it is ‘noninformative,’ so there are some considerations about cost in that context,” he said. For men with intermediate or high-risk disease, however, currently available tests are not good at predicting what an individual patient’s response would be to a specific type of therapy, whether surgery, radiation, androgen deprivation, chemotherapy, or a combination.
“This is an area where predictive biomarkers would be very informative. There is ongoing research, and I think this is an area of potentially large advancement in how we risk-stratify our patients,” Dr. Ross said.
HOLLYWOOD, FLA. – Current evidence suggests that molecular tests for prostate cancer are prognostic and can help clinicians and patients with difficult treatment decisions. In the not-too-distant future, gene tests could also guide choice of therapies.
“I think that the largest impact is going to come in areas of both the greatest treatment uncertainty and areas where we can be predictive about the response to treatment,” said Dr. Ashley Ross, a urologic oncologist and pathologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore.
Multigene panels may soon be able help identify which patients might benefit more from radical prostatectomy or radiation therapy, whether radiation therapy effects could be enhanced with the addition of androgen-deprivation therapy, and whether early use of docetaxel might add therapeutic benefit, he said at the annual conference of the National Comprehensive Cancer Network.
The 2016 iteration of the NCCN guidelines for the treatment of prostate cancer include a note stating that “men with clinically localized disease may consider the use of tumor-based molecular assays. Retrospective case cohort studies have shown that molecular assays performed on biopsy or prostatectomy specimens provide prognostic information independent of NCCN risk groups.”
The use of molecular assays may inform treatment decisions by helping to predict the likelihood of death if a patient is managed conservatively, risks for biochemical progression after radical prostatectomy or external beam therapy, and the likelihood that a patient could develop metastatic disease after radical prostatectomy or salvage radiotherapy, the guidelines say.
Dr. Ross reviewed the molecular biology of localized prostate cancer and the benefits and risks of currently available molecular tests.
“We’ve had an increased ability to get molecular information or genomic information from very limited amounts of routinely-stored pathologic tissue, and that’s resulted in the generation of many molecular-based tissue tests in prostate cancer. With the emergence of those tests and a lot of aggressive marketing, there has been a lot of confusion for patients and providers about whether we should use them or not and in what context,” he said.
Prostate cancer is genomically complex, even in the localized stage, with copy number alterations, deletions, and amplifications; chromosomal rearrangements; and point mutations, he said.
One of the best characterized genomic events is the early loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog). This gene works within the PI3 kinase (PI3K)/AKT pathway. PI3K pathway mutations have been identified in up to 40% of all primary prostate cancers and 100% of mutations, Dr. Ross explained.
Loss of PTEN itself has been detected in about 15%-40% of primary prostate cancers and 50% of metastases, and the loss correlates with disease stage and tumor grade.
The NCCN guidelines list six available tissue-based tests for prostate cancer prognosis, including tests based on general cancer features such as cell-cycle proliferation, and those based on specific molecular features of cancer.
An example of the general type of test is the Ki-67 immunohistochemistry (IHC) test, which looks for a cellular marker of proliferation, and has been shown to have independent prognostic significance after radiation therapy or radical prostatectomy. This test is not currently recommended by the Medicare Molecular Diagnostic Services (MolDx) program, however.
Another general-type test is the Polaris quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) panel, which tests for 31 cell-cycle-related genes and 15 “housekeeping” controls. This test is recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy. It has been shown to independently predict prostate cancer–specific mortality, biochemical failure/recurrence, and metastasis, the guidelines say.
Tests based on molecular features include:
• PTEN/ERG, an IHC or fluorescent in situ hybridization test that has been shown to predict prostate cancer–specific mortality, upgrading to Gleason pattern 4 on radical prostatectomy, and biochemical recurrence (not MolDx recommended).
• Decipher, a whole-transcriptome 1.4M RNA expression oligonucleotide microarray shown to predict biochemical failure, metastasis, and prostate cancer–specific mortality (recommended for postradical prostatectomy for patients with pT2 tumors with positive margins, and pT3 disease, and rising PSA above nadir);
• Oncotype DX, an RT-PCR assay for 12 prostate cancer genes and five housekeeping controls (recommended for post-biopsy evaluation of men with very-low-risk or low-risk prostate cancer who at the time of diagnosis have at least 10 years of life expectancy).
• ProMark, multiplex immunofluorescent staining of eight proteins, which has been shown to independently predict non–organ-confined pT3 disease or Gleason pattern 4 disease on radical prostatectomy (not reviewed).
Dr. Ross said that in his practice, he generally does not order molecular testing for surveillance of men older than 65 who have very-low-risk disease. For men with low-risk disease, however, molecular testing may help in clinical decision making to predict upgrading or disease progression.
“There’s limited data from surveillance populations, but these tests can be used in this context with retrospective data available, realizing that in most cases the tests will be confirmative, or another way of thinking about it is ‘noninformative,’ so there are some considerations about cost in that context,” he said. For men with intermediate or high-risk disease, however, currently available tests are not good at predicting what an individual patient’s response would be to a specific type of therapy, whether surgery, radiation, androgen deprivation, chemotherapy, or a combination.
“This is an area where predictive biomarkers would be very informative. There is ongoing research, and I think this is an area of potentially large advancement in how we risk-stratify our patients,” Dr. Ross said.
EXPERT ANALYSIS FROM THE NCCN ANNUAL CONFERENCE
Guidelines highlight revolution in advanced melanoma therapies
HOLLYWOOD, FLA. –The remarkable changes that have occurred in the treatment of advanced malignant melanoma over the last several years are reflected in revised National Comprehensive Cancer Network guidelines.
“Gone are the days where our active agents were interferon and dacarbazine,” said Dr. John A. Thompson of the Fred Hutchinson Cancer Research Center, Seattle.
“We’ve seen the approval by the FDA of the PD-1-targeted agents and also molecular-targeted agents to treat patients with mutations in the BRAF gene, and the rate of change continues apace,” he said at the annual conference of the National Comprehensive Cancer Network.
Among the changes in the 2016 guidelines are the addition of high-dose ipilimumab (Yervoy) as an option for stage III (node-positive) disease, and intralesional talimogene laherparepvec (T-VEC) for primary treatment of stage III in-transit disease.
Guidelines for first-line systemic therapy for metastatic or unresectable disease recommend treatment based on evaluation of individual patients and include:
• Monotherapy with an anti-PD-1 (programmed death-1) agent, either pembrolizumab (Keytruda) or nivolumab (Opdivo) (category 1 recommendation).
• Targeted therapy for BRAF-mutated disease with combinations (preferred) of either dabrafenib (Tafinlar) and trametinib (Mekinist) or vemurafenib (Zelboraf)and cobimetinib (Cotellic); both are category 1 recommendations.
• Single-agent therapy with either vemurafenib or dabrafenib (category 1), or clinical trial.
For patients with disease progression or those who have had their maximum clinical benefit from BRAF-targeted therapy and good performance status (0-2), the guidelines recommend second-line or subsequent therapy with anti-PD-1 agents as above, ipilimumab, or a combination of nivolumab and ipilimumab.
The guidelines note, however, that “nivolumab/ipilimumab combination therapy is associated with improved relapse-free survival compared with single-agent nivolumab or ipilimumab, at the expense of significantly increased toxicity. Compared to single-agent therapy, the impact of nivolumab/ipilimumab combination therapy on overall survival is not known.”
Also recommended are targeted therapy with the BRAF-inhibitor combinations listed above (preferred) or single-agent therapy with vemurafenib or dabrafenib.
“In previously untreated patients with unresectable stage IIIC or stage IV disease, the combination of vemurafenib/cobimetinib was associated with improved PFS [progression-free survival] and response rate when compared to vemurafenib alone. The impact on overall survival compared to single-agent vemurafenib is unknown,” the guidelines state.
Other second-line options for patients with good performance status include high-dose interleukin-2 (not suitable for patients with inadequate organ reserve, poor performance status, or untreated or active brain metastases), biochemotherapy and cytotoxic agents (dacarbazine or temozolomide, and cisplatin or carboplatin, with or without vinblastine or nitrosourea, and IL-2 and interferon alfa-2b; paclitaxel, albumin-bound paclitaxel).
For patients with poor performance status (3-4) the guidelines call for best supportive care according to guidelines for palliative care.
Oncolytic immunotherapy
For treatment of recurrent disease, the guidelines newly recommend use of T-VEC, a genetically modified herpes simplex-1 virus that is injected intralesionally into accessible tumors. The attenuated virus does not kill healthy cells, but replicates in tumors and causes the cells to secrete granulocyte macrophage–colony stimulating factor (GM-CSF), leading to lysis of the tumor cells.
“It is hypothesized that the GM-CSF works with the immune system to boost a resident immune response against the destroyed melanoma cells and antigens that are released from this process,” Dr. Thompson said.
In a recent clinical trial (J Clin Oncol. 2015;33:2780-8), patients with injectable melanoma that was not surgically resectable were randomized to either intralesional T-VEC injections on week 0, 3, and then every 2 weeks (295 patients), or subcutaneous GM-CSF 125 mcg/m2 on days 1 to 14 for every 28 days (141 patients).
T-VEC was associated with significantly more durables responses (16% vs. 2.1% for GM-CSF, P less than .001) and a significantly higher overall response rate (26.4% vs. 5.7%, respectively, P less than .001).
In the primary analysis in an intent-to-treat population, T-VEC had a borderline significant association with better overall survival (median 23.2 vs. 18.9 months, hazard ratio [HR] 0.70, log-rank P = .051).
In subanalyses of outcomes in patient subgroups, however, the benefits of T-VEC were seen in patients with stage IIIB IIIC, and IV M1a disease (HR 0.57, P less than .001), but not in patients with IV M1b or M1c disease. In addition, patients treated with T-VEC in first-line therapy had significantly better overall survival compared with GM-CSF (HR 0.50, P less than .001), but those who received it in second or subsequent lines of therapy saw no survival benefit from intralesional injection.
Future directions for the treatment of advanced melanoma include identification of predictive biomarkers to guide the choice of therapy, new immune agonist antibodies or checkpoint inhibitors to act in concert with PD-1 inhibitors, adaptive T-cell therapies, and lymphokines, cytokines, vaccines, and targeted therapies that can overcome mechanisms of resistance and work in combination with immunomodulators, Dr. Thompson said.
HOLLYWOOD, FLA. –The remarkable changes that have occurred in the treatment of advanced malignant melanoma over the last several years are reflected in revised National Comprehensive Cancer Network guidelines.
“Gone are the days where our active agents were interferon and dacarbazine,” said Dr. John A. Thompson of the Fred Hutchinson Cancer Research Center, Seattle.
“We’ve seen the approval by the FDA of the PD-1-targeted agents and also molecular-targeted agents to treat patients with mutations in the BRAF gene, and the rate of change continues apace,” he said at the annual conference of the National Comprehensive Cancer Network.
Among the changes in the 2016 guidelines are the addition of high-dose ipilimumab (Yervoy) as an option for stage III (node-positive) disease, and intralesional talimogene laherparepvec (T-VEC) for primary treatment of stage III in-transit disease.
Guidelines for first-line systemic therapy for metastatic or unresectable disease recommend treatment based on evaluation of individual patients and include:
• Monotherapy with an anti-PD-1 (programmed death-1) agent, either pembrolizumab (Keytruda) or nivolumab (Opdivo) (category 1 recommendation).
• Targeted therapy for BRAF-mutated disease with combinations (preferred) of either dabrafenib (Tafinlar) and trametinib (Mekinist) or vemurafenib (Zelboraf)and cobimetinib (Cotellic); both are category 1 recommendations.
• Single-agent therapy with either vemurafenib or dabrafenib (category 1), or clinical trial.
For patients with disease progression or those who have had their maximum clinical benefit from BRAF-targeted therapy and good performance status (0-2), the guidelines recommend second-line or subsequent therapy with anti-PD-1 agents as above, ipilimumab, or a combination of nivolumab and ipilimumab.
The guidelines note, however, that “nivolumab/ipilimumab combination therapy is associated with improved relapse-free survival compared with single-agent nivolumab or ipilimumab, at the expense of significantly increased toxicity. Compared to single-agent therapy, the impact of nivolumab/ipilimumab combination therapy on overall survival is not known.”
Also recommended are targeted therapy with the BRAF-inhibitor combinations listed above (preferred) or single-agent therapy with vemurafenib or dabrafenib.
“In previously untreated patients with unresectable stage IIIC or stage IV disease, the combination of vemurafenib/cobimetinib was associated with improved PFS [progression-free survival] and response rate when compared to vemurafenib alone. The impact on overall survival compared to single-agent vemurafenib is unknown,” the guidelines state.
Other second-line options for patients with good performance status include high-dose interleukin-2 (not suitable for patients with inadequate organ reserve, poor performance status, or untreated or active brain metastases), biochemotherapy and cytotoxic agents (dacarbazine or temozolomide, and cisplatin or carboplatin, with or without vinblastine or nitrosourea, and IL-2 and interferon alfa-2b; paclitaxel, albumin-bound paclitaxel).
For patients with poor performance status (3-4) the guidelines call for best supportive care according to guidelines for palliative care.
Oncolytic immunotherapy
For treatment of recurrent disease, the guidelines newly recommend use of T-VEC, a genetically modified herpes simplex-1 virus that is injected intralesionally into accessible tumors. The attenuated virus does not kill healthy cells, but replicates in tumors and causes the cells to secrete granulocyte macrophage–colony stimulating factor (GM-CSF), leading to lysis of the tumor cells.
“It is hypothesized that the GM-CSF works with the immune system to boost a resident immune response against the destroyed melanoma cells and antigens that are released from this process,” Dr. Thompson said.
In a recent clinical trial (J Clin Oncol. 2015;33:2780-8), patients with injectable melanoma that was not surgically resectable were randomized to either intralesional T-VEC injections on week 0, 3, and then every 2 weeks (295 patients), or subcutaneous GM-CSF 125 mcg/m2 on days 1 to 14 for every 28 days (141 patients).
T-VEC was associated with significantly more durables responses (16% vs. 2.1% for GM-CSF, P less than .001) and a significantly higher overall response rate (26.4% vs. 5.7%, respectively, P less than .001).
In the primary analysis in an intent-to-treat population, T-VEC had a borderline significant association with better overall survival (median 23.2 vs. 18.9 months, hazard ratio [HR] 0.70, log-rank P = .051).
In subanalyses of outcomes in patient subgroups, however, the benefits of T-VEC were seen in patients with stage IIIB IIIC, and IV M1a disease (HR 0.57, P less than .001), but not in patients with IV M1b or M1c disease. In addition, patients treated with T-VEC in first-line therapy had significantly better overall survival compared with GM-CSF (HR 0.50, P less than .001), but those who received it in second or subsequent lines of therapy saw no survival benefit from intralesional injection.
Future directions for the treatment of advanced melanoma include identification of predictive biomarkers to guide the choice of therapy, new immune agonist antibodies or checkpoint inhibitors to act in concert with PD-1 inhibitors, adaptive T-cell therapies, and lymphokines, cytokines, vaccines, and targeted therapies that can overcome mechanisms of resistance and work in combination with immunomodulators, Dr. Thompson said.
HOLLYWOOD, FLA. –The remarkable changes that have occurred in the treatment of advanced malignant melanoma over the last several years are reflected in revised National Comprehensive Cancer Network guidelines.
“Gone are the days where our active agents were interferon and dacarbazine,” said Dr. John A. Thompson of the Fred Hutchinson Cancer Research Center, Seattle.
“We’ve seen the approval by the FDA of the PD-1-targeted agents and also molecular-targeted agents to treat patients with mutations in the BRAF gene, and the rate of change continues apace,” he said at the annual conference of the National Comprehensive Cancer Network.
Among the changes in the 2016 guidelines are the addition of high-dose ipilimumab (Yervoy) as an option for stage III (node-positive) disease, and intralesional talimogene laherparepvec (T-VEC) for primary treatment of stage III in-transit disease.
Guidelines for first-line systemic therapy for metastatic or unresectable disease recommend treatment based on evaluation of individual patients and include:
• Monotherapy with an anti-PD-1 (programmed death-1) agent, either pembrolizumab (Keytruda) or nivolumab (Opdivo) (category 1 recommendation).
• Targeted therapy for BRAF-mutated disease with combinations (preferred) of either dabrafenib (Tafinlar) and trametinib (Mekinist) or vemurafenib (Zelboraf)and cobimetinib (Cotellic); both are category 1 recommendations.
• Single-agent therapy with either vemurafenib or dabrafenib (category 1), or clinical trial.
For patients with disease progression or those who have had their maximum clinical benefit from BRAF-targeted therapy and good performance status (0-2), the guidelines recommend second-line or subsequent therapy with anti-PD-1 agents as above, ipilimumab, or a combination of nivolumab and ipilimumab.
The guidelines note, however, that “nivolumab/ipilimumab combination therapy is associated with improved relapse-free survival compared with single-agent nivolumab or ipilimumab, at the expense of significantly increased toxicity. Compared to single-agent therapy, the impact of nivolumab/ipilimumab combination therapy on overall survival is not known.”
Also recommended are targeted therapy with the BRAF-inhibitor combinations listed above (preferred) or single-agent therapy with vemurafenib or dabrafenib.
“In previously untreated patients with unresectable stage IIIC or stage IV disease, the combination of vemurafenib/cobimetinib was associated with improved PFS [progression-free survival] and response rate when compared to vemurafenib alone. The impact on overall survival compared to single-agent vemurafenib is unknown,” the guidelines state.
Other second-line options for patients with good performance status include high-dose interleukin-2 (not suitable for patients with inadequate organ reserve, poor performance status, or untreated or active brain metastases), biochemotherapy and cytotoxic agents (dacarbazine or temozolomide, and cisplatin or carboplatin, with or without vinblastine or nitrosourea, and IL-2 and interferon alfa-2b; paclitaxel, albumin-bound paclitaxel).
For patients with poor performance status (3-4) the guidelines call for best supportive care according to guidelines for palliative care.
Oncolytic immunotherapy
For treatment of recurrent disease, the guidelines newly recommend use of T-VEC, a genetically modified herpes simplex-1 virus that is injected intralesionally into accessible tumors. The attenuated virus does not kill healthy cells, but replicates in tumors and causes the cells to secrete granulocyte macrophage–colony stimulating factor (GM-CSF), leading to lysis of the tumor cells.
“It is hypothesized that the GM-CSF works with the immune system to boost a resident immune response against the destroyed melanoma cells and antigens that are released from this process,” Dr. Thompson said.
In a recent clinical trial (J Clin Oncol. 2015;33:2780-8), patients with injectable melanoma that was not surgically resectable were randomized to either intralesional T-VEC injections on week 0, 3, and then every 2 weeks (295 patients), or subcutaneous GM-CSF 125 mcg/m2 on days 1 to 14 for every 28 days (141 patients).
T-VEC was associated with significantly more durables responses (16% vs. 2.1% for GM-CSF, P less than .001) and a significantly higher overall response rate (26.4% vs. 5.7%, respectively, P less than .001).
In the primary analysis in an intent-to-treat population, T-VEC had a borderline significant association with better overall survival (median 23.2 vs. 18.9 months, hazard ratio [HR] 0.70, log-rank P = .051).
In subanalyses of outcomes in patient subgroups, however, the benefits of T-VEC were seen in patients with stage IIIB IIIC, and IV M1a disease (HR 0.57, P less than .001), but not in patients with IV M1b or M1c disease. In addition, patients treated with T-VEC in first-line therapy had significantly better overall survival compared with GM-CSF (HR 0.50, P less than .001), but those who received it in second or subsequent lines of therapy saw no survival benefit from intralesional injection.
Future directions for the treatment of advanced melanoma include identification of predictive biomarkers to guide the choice of therapy, new immune agonist antibodies or checkpoint inhibitors to act in concert with PD-1 inhibitors, adaptive T-cell therapies, and lymphokines, cytokines, vaccines, and targeted therapies that can overcome mechanisms of resistance and work in combination with immunomodulators, Dr. Thompson said.
AT THE NCCN ANNUAL CONFERENCE
Key clinical point: Immunotherapies and targeted agents have revolutionized the treatment of advanced melanoma.
Major finding: Current therapies are associated with response rates ranging from 60% to 75%.
Data source: Review of NCCN melanoma guideline changes and evidence supporting the changes.
Disclosures: Dr. Thompson disclosed consulting fees or honoraria from Eisai, Genentech, and Seattle Genetics, and “other financial benefit” from Celidex Therapeutics.
New vulvar cancer guidelines stress regional disease control
HOLLYWOOD, FLA. – The National Comprehensive Cancer Network has issued new guidelines for the diagnosis and management of vulvar cancer.
Vulvar cancers are rare neoplasms, with an estimated U.S. annual incidence of 5,950 cases, and 1,110 deaths. The majority of cases (about 90%) are of squamous cell histology.
Treatment of vulvar cancer has evolved from en bloc resections used throughout most of the 20th century, to more refined techniques, said Dr. Benjamin E. Greer, professor of gynecological oncology at the University of Washington in Seattle.
“In the 1980s, we started to modify treatment to reduce morbidity,” he said at the annual conference of the National Comprehensive Cancer Network.
With older, more radical techniques, groin breakdown, leg edema, and impaired sexual function were common post-surgery consequences. Current practice, however, is to perform regional lymph node management for unilateral cancers, radical local excision rather than en bloc resections, separate groin incisions, lymphatic mapping, radiation, chemotherapy, and, if necessary, exenteration, Dr. Greer noted.
The guidelines note that adequate surgical margins – 1 to 2 cm – at the time of primary surgery appear to be essential for reducing risk of local recurrence, and that if margins are within 8 mm of tumor, the surgeon should consider re-excision or adjuvant radiation.
Lymph node status is the most important determinant of survival, with historical reports showing overall survival following surgery of 70% to 80% among patients with negative nodes, compared with 30% to 40% of those with positive nodes, he said.
Evaluation of bilateral inguinofemoral groin nodes should be performed in patients with lesions in the vulvar midline, and ipsilateral groin node evaluation should be performed for those with lateral lesions lying more than 2 cm from the vulvar midline. Additionally, select patients may require sentinel lymph node biopsy, the guidelines state.
Unilateral carcinomas of the vulva can be treated with limited radical vulvectomy and ipsilateral inguinal femoral node dissection. Lymph node dissection can be performed through a separate incision. For patients with positive nodes, adjuvant radiation may aid in disease control. Patients with inoperable carcinomas are recommended to receive radiation and chemotherapy.
Radiation for vulvar cancer
“For early stage tumors, adjuvant radiotherapy is an effective treatment modality that significantly decreases recurrence, especially in surgically resected groins, and it leads to improvement in relapse-free and overall survival,” said Dr. Wui-Jin Koh, medical director for radiation oncology at the Fred Hutchinson Cancer Research Center in Seattle.
Concurrent chemotherapy and radiation may provide additional therapeutic benefit, especially for patients with advanced, unresectable tumors, and it may help to address systemic risk in patients with multiple positive lymph nodes, Dr. Koh said.
The guidelines state that radiation can be given with external beam radiation delivered via a 3D-conformal or intensity modulated (IMRT) technique, with brachytherapy boost for some tumors where the anatomy permits.
“Careful attention should be taken to ensure adequate tumor coverage by combining clinical examination, imaging findings, and appropriate nodal volumes at risk to define the target volume,” the guideline states.
For adjuvant therapy, doses of 50.4 Gy divided in 1.8 Gy fractions should be delivered once daily 5 days per week, with minimal treatment breaks.
For treatment of unresectable tumors, doses range from 59.4 Gy to 64.8 Gy in 1.8 Gy fractions, with a boost dose to approximately 70 Gy for large lymph nodes in select cases.
Residual disease
The decision to provide additional treatment following surgery is based on whether the patient is clinically negative for residual tumor at the primary site and nodes.
“If one has negative margins and negative nodes? Observation, absolutely,” Dr. Koh said. “If one has positive margins for invasive disease, our recommendation is to re-excise and not go straight to radiation, and if one can do it and get negative margins, again observe the majority of them.”
“Use radiation very judiciously,” he added. “Only if patients have positive margins or have unresectable primary disease do we routinely recommend radiation.”
Locally advanced disease
For patients who cannot be treated with conventional or sphincter-sparing, organ preserving surgery upfront, the recommendation is to provide chemoradiation, with initial radiation to the primary site, groins, and pelvis, and concurrent week cisplatin at a dose of 30-40 mg/m2 per week. The recommended radiation doses are 45 Gy to at-risk, microscopic clinical tumor volume, and 57.6 to 60 Gy to gross tumor volume (primary site and nodes).
“If one uses IMRT, you need to be very generous with the volumes,” Dr. Koh said.
The panelists also recommend re-imaging and re-evaluating patients 6 to 8 weeks after the completion of chemoradiation, with possible resection or biopsy of the primary tumor site, and limited groin resection of imaged residual disease.
For patients with clearly node-positive disease, “my general preference is to give upfront chemoradiation therapy to avoid delay of primary therapy, and then resect residual nodes after the chemoradiation is done,” he said.
HOLLYWOOD, FLA. – The National Comprehensive Cancer Network has issued new guidelines for the diagnosis and management of vulvar cancer.
Vulvar cancers are rare neoplasms, with an estimated U.S. annual incidence of 5,950 cases, and 1,110 deaths. The majority of cases (about 90%) are of squamous cell histology.
Treatment of vulvar cancer has evolved from en bloc resections used throughout most of the 20th century, to more refined techniques, said Dr. Benjamin E. Greer, professor of gynecological oncology at the University of Washington in Seattle.
“In the 1980s, we started to modify treatment to reduce morbidity,” he said at the annual conference of the National Comprehensive Cancer Network.
With older, more radical techniques, groin breakdown, leg edema, and impaired sexual function were common post-surgery consequences. Current practice, however, is to perform regional lymph node management for unilateral cancers, radical local excision rather than en bloc resections, separate groin incisions, lymphatic mapping, radiation, chemotherapy, and, if necessary, exenteration, Dr. Greer noted.
The guidelines note that adequate surgical margins – 1 to 2 cm – at the time of primary surgery appear to be essential for reducing risk of local recurrence, and that if margins are within 8 mm of tumor, the surgeon should consider re-excision or adjuvant radiation.
Lymph node status is the most important determinant of survival, with historical reports showing overall survival following surgery of 70% to 80% among patients with negative nodes, compared with 30% to 40% of those with positive nodes, he said.
Evaluation of bilateral inguinofemoral groin nodes should be performed in patients with lesions in the vulvar midline, and ipsilateral groin node evaluation should be performed for those with lateral lesions lying more than 2 cm from the vulvar midline. Additionally, select patients may require sentinel lymph node biopsy, the guidelines state.
Unilateral carcinomas of the vulva can be treated with limited radical vulvectomy and ipsilateral inguinal femoral node dissection. Lymph node dissection can be performed through a separate incision. For patients with positive nodes, adjuvant radiation may aid in disease control. Patients with inoperable carcinomas are recommended to receive radiation and chemotherapy.
Radiation for vulvar cancer
“For early stage tumors, adjuvant radiotherapy is an effective treatment modality that significantly decreases recurrence, especially in surgically resected groins, and it leads to improvement in relapse-free and overall survival,” said Dr. Wui-Jin Koh, medical director for radiation oncology at the Fred Hutchinson Cancer Research Center in Seattle.
Concurrent chemotherapy and radiation may provide additional therapeutic benefit, especially for patients with advanced, unresectable tumors, and it may help to address systemic risk in patients with multiple positive lymph nodes, Dr. Koh said.
The guidelines state that radiation can be given with external beam radiation delivered via a 3D-conformal or intensity modulated (IMRT) technique, with brachytherapy boost for some tumors where the anatomy permits.
“Careful attention should be taken to ensure adequate tumor coverage by combining clinical examination, imaging findings, and appropriate nodal volumes at risk to define the target volume,” the guideline states.
For adjuvant therapy, doses of 50.4 Gy divided in 1.8 Gy fractions should be delivered once daily 5 days per week, with minimal treatment breaks.
For treatment of unresectable tumors, doses range from 59.4 Gy to 64.8 Gy in 1.8 Gy fractions, with a boost dose to approximately 70 Gy for large lymph nodes in select cases.
Residual disease
The decision to provide additional treatment following surgery is based on whether the patient is clinically negative for residual tumor at the primary site and nodes.
“If one has negative margins and negative nodes? Observation, absolutely,” Dr. Koh said. “If one has positive margins for invasive disease, our recommendation is to re-excise and not go straight to radiation, and if one can do it and get negative margins, again observe the majority of them.”
“Use radiation very judiciously,” he added. “Only if patients have positive margins or have unresectable primary disease do we routinely recommend radiation.”
Locally advanced disease
For patients who cannot be treated with conventional or sphincter-sparing, organ preserving surgery upfront, the recommendation is to provide chemoradiation, with initial radiation to the primary site, groins, and pelvis, and concurrent week cisplatin at a dose of 30-40 mg/m2 per week. The recommended radiation doses are 45 Gy to at-risk, microscopic clinical tumor volume, and 57.6 to 60 Gy to gross tumor volume (primary site and nodes).
“If one uses IMRT, you need to be very generous with the volumes,” Dr. Koh said.
The panelists also recommend re-imaging and re-evaluating patients 6 to 8 weeks after the completion of chemoradiation, with possible resection or biopsy of the primary tumor site, and limited groin resection of imaged residual disease.
For patients with clearly node-positive disease, “my general preference is to give upfront chemoradiation therapy to avoid delay of primary therapy, and then resect residual nodes after the chemoradiation is done,” he said.
HOLLYWOOD, FLA. – The National Comprehensive Cancer Network has issued new guidelines for the diagnosis and management of vulvar cancer.
Vulvar cancers are rare neoplasms, with an estimated U.S. annual incidence of 5,950 cases, and 1,110 deaths. The majority of cases (about 90%) are of squamous cell histology.
Treatment of vulvar cancer has evolved from en bloc resections used throughout most of the 20th century, to more refined techniques, said Dr. Benjamin E. Greer, professor of gynecological oncology at the University of Washington in Seattle.
“In the 1980s, we started to modify treatment to reduce morbidity,” he said at the annual conference of the National Comprehensive Cancer Network.
With older, more radical techniques, groin breakdown, leg edema, and impaired sexual function were common post-surgery consequences. Current practice, however, is to perform regional lymph node management for unilateral cancers, radical local excision rather than en bloc resections, separate groin incisions, lymphatic mapping, radiation, chemotherapy, and, if necessary, exenteration, Dr. Greer noted.
The guidelines note that adequate surgical margins – 1 to 2 cm – at the time of primary surgery appear to be essential for reducing risk of local recurrence, and that if margins are within 8 mm of tumor, the surgeon should consider re-excision or adjuvant radiation.
Lymph node status is the most important determinant of survival, with historical reports showing overall survival following surgery of 70% to 80% among patients with negative nodes, compared with 30% to 40% of those with positive nodes, he said.
Evaluation of bilateral inguinofemoral groin nodes should be performed in patients with lesions in the vulvar midline, and ipsilateral groin node evaluation should be performed for those with lateral lesions lying more than 2 cm from the vulvar midline. Additionally, select patients may require sentinel lymph node biopsy, the guidelines state.
Unilateral carcinomas of the vulva can be treated with limited radical vulvectomy and ipsilateral inguinal femoral node dissection. Lymph node dissection can be performed through a separate incision. For patients with positive nodes, adjuvant radiation may aid in disease control. Patients with inoperable carcinomas are recommended to receive radiation and chemotherapy.
Radiation for vulvar cancer
“For early stage tumors, adjuvant radiotherapy is an effective treatment modality that significantly decreases recurrence, especially in surgically resected groins, and it leads to improvement in relapse-free and overall survival,” said Dr. Wui-Jin Koh, medical director for radiation oncology at the Fred Hutchinson Cancer Research Center in Seattle.
Concurrent chemotherapy and radiation may provide additional therapeutic benefit, especially for patients with advanced, unresectable tumors, and it may help to address systemic risk in patients with multiple positive lymph nodes, Dr. Koh said.
The guidelines state that radiation can be given with external beam radiation delivered via a 3D-conformal or intensity modulated (IMRT) technique, with brachytherapy boost for some tumors where the anatomy permits.
“Careful attention should be taken to ensure adequate tumor coverage by combining clinical examination, imaging findings, and appropriate nodal volumes at risk to define the target volume,” the guideline states.
For adjuvant therapy, doses of 50.4 Gy divided in 1.8 Gy fractions should be delivered once daily 5 days per week, with minimal treatment breaks.
For treatment of unresectable tumors, doses range from 59.4 Gy to 64.8 Gy in 1.8 Gy fractions, with a boost dose to approximately 70 Gy for large lymph nodes in select cases.
Residual disease
The decision to provide additional treatment following surgery is based on whether the patient is clinically negative for residual tumor at the primary site and nodes.
“If one has negative margins and negative nodes? Observation, absolutely,” Dr. Koh said. “If one has positive margins for invasive disease, our recommendation is to re-excise and not go straight to radiation, and if one can do it and get negative margins, again observe the majority of them.”
“Use radiation very judiciously,” he added. “Only if patients have positive margins or have unresectable primary disease do we routinely recommend radiation.”
Locally advanced disease
For patients who cannot be treated with conventional or sphincter-sparing, organ preserving surgery upfront, the recommendation is to provide chemoradiation, with initial radiation to the primary site, groins, and pelvis, and concurrent week cisplatin at a dose of 30-40 mg/m2 per week. The recommended radiation doses are 45 Gy to at-risk, microscopic clinical tumor volume, and 57.6 to 60 Gy to gross tumor volume (primary site and nodes).
“If one uses IMRT, you need to be very generous with the volumes,” Dr. Koh said.
The panelists also recommend re-imaging and re-evaluating patients 6 to 8 weeks after the completion of chemoradiation, with possible resection or biopsy of the primary tumor site, and limited groin resection of imaged residual disease.
For patients with clearly node-positive disease, “my general preference is to give upfront chemoradiation therapy to avoid delay of primary therapy, and then resect residual nodes after the chemoradiation is done,” he said.
AT THE NCCN ANNUAL CONFERENCE
Key clinical point: Nodal status is an important determinant of survival of patients with vulvar carcinomas.
Major finding: Historically, reported overall survival following surgery is 70% to 80% among patients with negative nodes, compared with 30% to 40% of those with positive nodes.
Data source: Review of new clinical guidelines for the management of patients with vulvar cancer.
Disclosures: Dr. Greer and Dr. Koh reported having no relevant clinical disclosures.
