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In active CLL with deletion 17p, consider trial enrollment
NEW YORK – Outside of clinical trials, therapy for early stage chronic lymphocytic leukemia in patients with deletion of the short arm of chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 requires the presence of active disease, according to Neil E. Kay, MD.
“Right now, we would propose that patients with del[17]p should have additional prognostic work-up. It’s very important to know if they are unmutated or mutated for the IgVH gene,” he said, adding that stimulated karyotype is also important to perform in those with del[17]p.
“The median overall survivorship in many phase II and phase III trials appears to be around 2 to 3 years,” he said.
Those with a chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 who receive chemoimmunotherapy very rarely achieve a complete response, or if they do they have a short duration of response, he added.
In treated patients, 17p deletion and p53 mutation are the most common abnormalities acquired during the course of the disease.
“Unfortunately there appears to be a selection pressure, and [in treated patients] the incidence of 17p and the p53 mutation has been reported up to 23%-44%. No one understands completely the biology of this, but it may be that subclones are present and expand, or that new mutations occur due to selection pressure of [chemoimmunotherapy] and the overgrowth of these subclones,” he said.
Importantly, not all patients with del[17]p or p53 mutation have bad outcomes; there are patients with indolent disease, he noted, adding that various criteria have been shown to help identify which patients are at risk for poor outcomes and to classify them according to risk. In general, lower-risk patients have mutated immunoglobulin heavy chain variable gene status, early stage disease, younger age, good performance status, and normal serum lactate dehydrogenase. These criteria could be used to identify low-risk patients who can be followed, he said.
Fluorescence in situ hybridization (FISH) evaluation of patients is a useful tool when there is no access to sequencing and other tests, Dr. Kay said, describing a recent multinational CLL Research Consortium study of nearly 1,600 patients (Br J Haematol. 2016 Apr;173[1]:105-13).
In that study, he and his colleagues found that patients with less than 50% 17p did not have such poor outcomes, but at 50%-plus they did much worse in terms of time to first treatment.
Based on the available data, Dr. Kay said that treatment is unnecessary in asymptomatic patients, except, perhaps, in high-risk patients identified using recently published risk models, for whom clinical trial enrollment may be considered.
“We do advocate having a discussion about allogeneic stem cell transplant since this may still be the only curative approach,” he added.
In patients with del[17]p and/or p53 mutation who have progressive disease, Dr. Kay said his take on the available data is that patients should first be categorized by age, then by whether they are fit or frail, and finally by whether or not they have del[17]p. Those under age 70 years without del[17]p and who have a mutated IgVH status should be considered for a clinical trial, and are also good candidates for chemoimmunotherapy. If they do have del[17]p or p53 mutation, consider clinical trial enrollment or treatment with ibrutinib, he said.
Fit patients in a complete response can be referred for transplant evaluation, but while the other treatments can be considered in frail patients or those aged 70 years or older, transplant is not advised, he added.
For relapsed or refractory patients, FISH testing should be performed or repeated, because such patients are at high risk of progression to develop del[17]p or mutation, he noted.
Those who are asymptomatic can be observed or enrolled in a clinical trial, and those who are symptomatic can be enrolled in a clinical trial or treated with various novel agents, including ibrutinib, idelalisib/rituximab, venetoclax, or combination therapies with methylpred–anti-CD20, or alemtuzumab with or without rituximab. Referral for transplant may be warranted in these patients if they are fit.
“Progressive CLL patients with 17p deletion/p53 mutations are much less likely to do well with chemoimmunotherapy, and novel inhibitors are effective, but we still need to enhance complete response rates and minimal residual disease-negative status for these high-risk patients,” he said.
Dr. Kay reported consulting for or receiving grant/research support from Acerta, Celgene, Gilead, Infinity, MorphoSys, Pharmacyclics, and Tolero.
NEW YORK – Outside of clinical trials, therapy for early stage chronic lymphocytic leukemia in patients with deletion of the short arm of chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 requires the presence of active disease, according to Neil E. Kay, MD.
“Right now, we would propose that patients with del[17]p should have additional prognostic work-up. It’s very important to know if they are unmutated or mutated for the IgVH gene,” he said, adding that stimulated karyotype is also important to perform in those with del[17]p.
“The median overall survivorship in many phase II and phase III trials appears to be around 2 to 3 years,” he said.
Those with a chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 who receive chemoimmunotherapy very rarely achieve a complete response, or if they do they have a short duration of response, he added.
In treated patients, 17p deletion and p53 mutation are the most common abnormalities acquired during the course of the disease.
“Unfortunately there appears to be a selection pressure, and [in treated patients] the incidence of 17p and the p53 mutation has been reported up to 23%-44%. No one understands completely the biology of this, but it may be that subclones are present and expand, or that new mutations occur due to selection pressure of [chemoimmunotherapy] and the overgrowth of these subclones,” he said.
Importantly, not all patients with del[17]p or p53 mutation have bad outcomes; there are patients with indolent disease, he noted, adding that various criteria have been shown to help identify which patients are at risk for poor outcomes and to classify them according to risk. In general, lower-risk patients have mutated immunoglobulin heavy chain variable gene status, early stage disease, younger age, good performance status, and normal serum lactate dehydrogenase. These criteria could be used to identify low-risk patients who can be followed, he said.
Fluorescence in situ hybridization (FISH) evaluation of patients is a useful tool when there is no access to sequencing and other tests, Dr. Kay said, describing a recent multinational CLL Research Consortium study of nearly 1,600 patients (Br J Haematol. 2016 Apr;173[1]:105-13).
In that study, he and his colleagues found that patients with less than 50% 17p did not have such poor outcomes, but at 50%-plus they did much worse in terms of time to first treatment.
Based on the available data, Dr. Kay said that treatment is unnecessary in asymptomatic patients, except, perhaps, in high-risk patients identified using recently published risk models, for whom clinical trial enrollment may be considered.
“We do advocate having a discussion about allogeneic stem cell transplant since this may still be the only curative approach,” he added.
In patients with del[17]p and/or p53 mutation who have progressive disease, Dr. Kay said his take on the available data is that patients should first be categorized by age, then by whether they are fit or frail, and finally by whether or not they have del[17]p. Those under age 70 years without del[17]p and who have a mutated IgVH status should be considered for a clinical trial, and are also good candidates for chemoimmunotherapy. If they do have del[17]p or p53 mutation, consider clinical trial enrollment or treatment with ibrutinib, he said.
Fit patients in a complete response can be referred for transplant evaluation, but while the other treatments can be considered in frail patients or those aged 70 years or older, transplant is not advised, he added.
For relapsed or refractory patients, FISH testing should be performed or repeated, because such patients are at high risk of progression to develop del[17]p or mutation, he noted.
Those who are asymptomatic can be observed or enrolled in a clinical trial, and those who are symptomatic can be enrolled in a clinical trial or treated with various novel agents, including ibrutinib, idelalisib/rituximab, venetoclax, or combination therapies with methylpred–anti-CD20, or alemtuzumab with or without rituximab. Referral for transplant may be warranted in these patients if they are fit.
“Progressive CLL patients with 17p deletion/p53 mutations are much less likely to do well with chemoimmunotherapy, and novel inhibitors are effective, but we still need to enhance complete response rates and minimal residual disease-negative status for these high-risk patients,” he said.
Dr. Kay reported consulting for or receiving grant/research support from Acerta, Celgene, Gilead, Infinity, MorphoSys, Pharmacyclics, and Tolero.
NEW YORK – Outside of clinical trials, therapy for early stage chronic lymphocytic leukemia in patients with deletion of the short arm of chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 requires the presence of active disease, according to Neil E. Kay, MD.
“Right now, we would propose that patients with del[17]p should have additional prognostic work-up. It’s very important to know if they are unmutated or mutated for the IgVH gene,” he said, adding that stimulated karyotype is also important to perform in those with del[17]p.
“The median overall survivorship in many phase II and phase III trials appears to be around 2 to 3 years,” he said.
Those with a chromosome 17 (del[17]p) and/or mutation of the tumor suppressor gene TP53 who receive chemoimmunotherapy very rarely achieve a complete response, or if they do they have a short duration of response, he added.
In treated patients, 17p deletion and p53 mutation are the most common abnormalities acquired during the course of the disease.
“Unfortunately there appears to be a selection pressure, and [in treated patients] the incidence of 17p and the p53 mutation has been reported up to 23%-44%. No one understands completely the biology of this, but it may be that subclones are present and expand, or that new mutations occur due to selection pressure of [chemoimmunotherapy] and the overgrowth of these subclones,” he said.
Importantly, not all patients with del[17]p or p53 mutation have bad outcomes; there are patients with indolent disease, he noted, adding that various criteria have been shown to help identify which patients are at risk for poor outcomes and to classify them according to risk. In general, lower-risk patients have mutated immunoglobulin heavy chain variable gene status, early stage disease, younger age, good performance status, and normal serum lactate dehydrogenase. These criteria could be used to identify low-risk patients who can be followed, he said.
Fluorescence in situ hybridization (FISH) evaluation of patients is a useful tool when there is no access to sequencing and other tests, Dr. Kay said, describing a recent multinational CLL Research Consortium study of nearly 1,600 patients (Br J Haematol. 2016 Apr;173[1]:105-13).
In that study, he and his colleagues found that patients with less than 50% 17p did not have such poor outcomes, but at 50%-plus they did much worse in terms of time to first treatment.
Based on the available data, Dr. Kay said that treatment is unnecessary in asymptomatic patients, except, perhaps, in high-risk patients identified using recently published risk models, for whom clinical trial enrollment may be considered.
“We do advocate having a discussion about allogeneic stem cell transplant since this may still be the only curative approach,” he added.
In patients with del[17]p and/or p53 mutation who have progressive disease, Dr. Kay said his take on the available data is that patients should first be categorized by age, then by whether they are fit or frail, and finally by whether or not they have del[17]p. Those under age 70 years without del[17]p and who have a mutated IgVH status should be considered for a clinical trial, and are also good candidates for chemoimmunotherapy. If they do have del[17]p or p53 mutation, consider clinical trial enrollment or treatment with ibrutinib, he said.
Fit patients in a complete response can be referred for transplant evaluation, but while the other treatments can be considered in frail patients or those aged 70 years or older, transplant is not advised, he added.
For relapsed or refractory patients, FISH testing should be performed or repeated, because such patients are at high risk of progression to develop del[17]p or mutation, he noted.
Those who are asymptomatic can be observed or enrolled in a clinical trial, and those who are symptomatic can be enrolled in a clinical trial or treated with various novel agents, including ibrutinib, idelalisib/rituximab, venetoclax, or combination therapies with methylpred–anti-CD20, or alemtuzumab with or without rituximab. Referral for transplant may be warranted in these patients if they are fit.
“Progressive CLL patients with 17p deletion/p53 mutations are much less likely to do well with chemoimmunotherapy, and novel inhibitors are effective, but we still need to enhance complete response rates and minimal residual disease-negative status for these high-risk patients,” he said.
Dr. Kay reported consulting for or receiving grant/research support from Acerta, Celgene, Gilead, Infinity, MorphoSys, Pharmacyclics, and Tolero.
EXPERT ANALYSIS FROM LYMPHOMA & MYELOMA
In high-risk myeloma, look beyond VRD for induction
NEW YORK – There’s more to induction therapy for transplant-eligible multiple myeloma patients than the go-to combination of bortezomib, lenalidomide, and dexamethasone, commonly known as VRD, according to Joseph R. Mikhael, MD.
“Outstanding evidence” has emerged that demonstrates the value of combining multiple mechanisms of action, but there are numerous options available – there is a trend toward increasing use of carfilzomib, for example – and VRD isn’t necessarily the best option for all patients, nor is it available in all cases, Dr. Mikhael of Mayo Clinic Arizona, Scottsdale, said at an international congress on hematologic malignancies.
Further, choosing the treatment method shown to give the most powerful or deepest response as a default isn’t necessarily the best option, either, he said, noting data showing that the regimen most often associated with at least very good partial response (VGPR) after four cycles in newly diagnosed multiple myeloma (carfilzomib, lenalidomide, dexamethasone, or KRD, about a 90% response rate) costs 2.5 times more than does the regimen (lenalidomide, dexamethasone, or RD) that provided about a 50% response rate ($250,000 vs. $100,000 per year).“But it’s also the toxicity cost ... do we need that many [drugs]?” he said, adding that “just because a clinical trial shows that three drugs work better than two, it doesn’t mean that every time I have a patient who is eligible I’m going to go with all three.”
It may be that a patient can start on two, with a third added if needed, he added.
“That being said, we want to maximize the synergy of those three, especially in high-risk patients,” he said.
Prior to 2016, popular regimens included CyBorD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone), which were commonly used worldwide. CTD (cyclophosphamide, thalidomide, dexamethasone) was used in Brazil and other countries where it was difficult to obtain bortezomib; VRD was “king of the hill” in the United States, and transplant was routinely recommended, Dr. Mikhael said.
A number of recent studies are changing that paradigm, he said.
One such study, the prospective randomized Intergroupe Francophone du Myélome (IFM) 2013-04 trial, showed that VTD is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) for induction in patients with de novo multiple myeloma. VGPR and PR rates were significantly superior in the VTD arm.
Of note, hematologic toxicity increased in the VCD arm, and the peripheral neuropathy rate was higher in the VTD arm. However, the study was conducted at a time when bortezomib was generally used twice weekly; now it is standard to use it once weekly and subcutaneously, which significantly reduces the risk of peripheral neuropathy.
The authors advocated the preferential use of VTD over VCD for induction, based on the synergistic effect of a proteasome inhibitor and immunomodulatory drug, Dr. Mikhael said.
“Meanwhile, back in the United States, many trials were starting to be built with VRD,” he said, noting that “really extraordinary” responses were seen in phase I and phase II studies.
Perhaps the VRD study (called RVD in this case) that is most cited is the phase III IFM 2009 study comparing RVD with and without autologous stem cell transplant in newly diagnosed younger multiple myeloma patients. Although final results are still pending, interim results reported at the American Society of Hematology 2015 meeting (abstract 391) have been very helpful, Dr. Mikhael said.
The authors reported a 31% reduction in the risk of progression or death with autologous stem cell transplant versus RVD alone in patients with newly diagnosed multiple myeloma, as well as improved rates of thrombotic thrombocytopenic purpura (TTP) and minimal residual disease negativity (MRD). Mortality rates were similar.
The findings show that transplantation is feasible (93%), and associated with acceptable mortality (1.4%), an increased rate of negative MRD versus with RVD alone (80% vs. 65%), an improved 4-year progression-free survival (47% vs. 35%), and improved 4-year TTP (49% vs. 35%).
“Here the question was not so much is RVD the standard ... but is RVD plus transplant superior to RVD alone,” he said.
Surprising to many, especially the “dissenters in the crowd” who thought perhaps RVD would be the death knell to autologous stem cell transplant, transplant actually significantly improved the depth of response, he added.
Median progression-free survival at 10 months was 43% with versus 34% without transplantation.
“So there was definitely an argument here that transplant remains the standard of care,” he said, noting that transplant should be considered as decisions are made about up-front therapy.
As for the trend of bringing carfilzomib in earlier on in treatment, a number of studies, including the phase II CYKLONE study by Dr. Mikhael and his colleagues, suggest it improves the rates of deep response; some show that is especially true when used with transplant.
One study looking at KRD showed that the regimen provides high rates of deep and durable responses with acceptable tolerability – a finding that needs confirmation in a randomized setting.
Other studies are comparing KRD and VRD, and KRD and KCyd (carfilzomib, cyclophosphamide), as well as adding monoclonal antibodies such as daratumumab to treatment regimens, and results are very much anticipated, Dr. Mikhael said.
Currently, however, VRD remains the standard of care in standard risk and intermediate risk patients.
“But consideration in the highest-risk patients should be given to something like KRD,” he said. “We still recommend transplant across the board, we still recommend some form of maintenance therapy, be it with lenalidomide for most patients, but potentially bortezomib combined with carfilzomib in the highest risk patients.”
Dr. Mikhael reported consulting for Abbvie, Celgene, Onyx, and Sanofi.
NEW YORK – There’s more to induction therapy for transplant-eligible multiple myeloma patients than the go-to combination of bortezomib, lenalidomide, and dexamethasone, commonly known as VRD, according to Joseph R. Mikhael, MD.
“Outstanding evidence” has emerged that demonstrates the value of combining multiple mechanisms of action, but there are numerous options available – there is a trend toward increasing use of carfilzomib, for example – and VRD isn’t necessarily the best option for all patients, nor is it available in all cases, Dr. Mikhael of Mayo Clinic Arizona, Scottsdale, said at an international congress on hematologic malignancies.
Further, choosing the treatment method shown to give the most powerful or deepest response as a default isn’t necessarily the best option, either, he said, noting data showing that the regimen most often associated with at least very good partial response (VGPR) after four cycles in newly diagnosed multiple myeloma (carfilzomib, lenalidomide, dexamethasone, or KRD, about a 90% response rate) costs 2.5 times more than does the regimen (lenalidomide, dexamethasone, or RD) that provided about a 50% response rate ($250,000 vs. $100,000 per year).“But it’s also the toxicity cost ... do we need that many [drugs]?” he said, adding that “just because a clinical trial shows that three drugs work better than two, it doesn’t mean that every time I have a patient who is eligible I’m going to go with all three.”
It may be that a patient can start on two, with a third added if needed, he added.
“That being said, we want to maximize the synergy of those three, especially in high-risk patients,” he said.
Prior to 2016, popular regimens included CyBorD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone), which were commonly used worldwide. CTD (cyclophosphamide, thalidomide, dexamethasone) was used in Brazil and other countries where it was difficult to obtain bortezomib; VRD was “king of the hill” in the United States, and transplant was routinely recommended, Dr. Mikhael said.
A number of recent studies are changing that paradigm, he said.
One such study, the prospective randomized Intergroupe Francophone du Myélome (IFM) 2013-04 trial, showed that VTD is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) for induction in patients with de novo multiple myeloma. VGPR and PR rates were significantly superior in the VTD arm.
Of note, hematologic toxicity increased in the VCD arm, and the peripheral neuropathy rate was higher in the VTD arm. However, the study was conducted at a time when bortezomib was generally used twice weekly; now it is standard to use it once weekly and subcutaneously, which significantly reduces the risk of peripheral neuropathy.
The authors advocated the preferential use of VTD over VCD for induction, based on the synergistic effect of a proteasome inhibitor and immunomodulatory drug, Dr. Mikhael said.
“Meanwhile, back in the United States, many trials were starting to be built with VRD,” he said, noting that “really extraordinary” responses were seen in phase I and phase II studies.
Perhaps the VRD study (called RVD in this case) that is most cited is the phase III IFM 2009 study comparing RVD with and without autologous stem cell transplant in newly diagnosed younger multiple myeloma patients. Although final results are still pending, interim results reported at the American Society of Hematology 2015 meeting (abstract 391) have been very helpful, Dr. Mikhael said.
The authors reported a 31% reduction in the risk of progression or death with autologous stem cell transplant versus RVD alone in patients with newly diagnosed multiple myeloma, as well as improved rates of thrombotic thrombocytopenic purpura (TTP) and minimal residual disease negativity (MRD). Mortality rates were similar.
The findings show that transplantation is feasible (93%), and associated with acceptable mortality (1.4%), an increased rate of negative MRD versus with RVD alone (80% vs. 65%), an improved 4-year progression-free survival (47% vs. 35%), and improved 4-year TTP (49% vs. 35%).
“Here the question was not so much is RVD the standard ... but is RVD plus transplant superior to RVD alone,” he said.
Surprising to many, especially the “dissenters in the crowd” who thought perhaps RVD would be the death knell to autologous stem cell transplant, transplant actually significantly improved the depth of response, he added.
Median progression-free survival at 10 months was 43% with versus 34% without transplantation.
“So there was definitely an argument here that transplant remains the standard of care,” he said, noting that transplant should be considered as decisions are made about up-front therapy.
As for the trend of bringing carfilzomib in earlier on in treatment, a number of studies, including the phase II CYKLONE study by Dr. Mikhael and his colleagues, suggest it improves the rates of deep response; some show that is especially true when used with transplant.
One study looking at KRD showed that the regimen provides high rates of deep and durable responses with acceptable tolerability – a finding that needs confirmation in a randomized setting.
Other studies are comparing KRD and VRD, and KRD and KCyd (carfilzomib, cyclophosphamide), as well as adding monoclonal antibodies such as daratumumab to treatment regimens, and results are very much anticipated, Dr. Mikhael said.
Currently, however, VRD remains the standard of care in standard risk and intermediate risk patients.
“But consideration in the highest-risk patients should be given to something like KRD,” he said. “We still recommend transplant across the board, we still recommend some form of maintenance therapy, be it with lenalidomide for most patients, but potentially bortezomib combined with carfilzomib in the highest risk patients.”
Dr. Mikhael reported consulting for Abbvie, Celgene, Onyx, and Sanofi.
NEW YORK – There’s more to induction therapy for transplant-eligible multiple myeloma patients than the go-to combination of bortezomib, lenalidomide, and dexamethasone, commonly known as VRD, according to Joseph R. Mikhael, MD.
“Outstanding evidence” has emerged that demonstrates the value of combining multiple mechanisms of action, but there are numerous options available – there is a trend toward increasing use of carfilzomib, for example – and VRD isn’t necessarily the best option for all patients, nor is it available in all cases, Dr. Mikhael of Mayo Clinic Arizona, Scottsdale, said at an international congress on hematologic malignancies.
Further, choosing the treatment method shown to give the most powerful or deepest response as a default isn’t necessarily the best option, either, he said, noting data showing that the regimen most often associated with at least very good partial response (VGPR) after four cycles in newly diagnosed multiple myeloma (carfilzomib, lenalidomide, dexamethasone, or KRD, about a 90% response rate) costs 2.5 times more than does the regimen (lenalidomide, dexamethasone, or RD) that provided about a 50% response rate ($250,000 vs. $100,000 per year).“But it’s also the toxicity cost ... do we need that many [drugs]?” he said, adding that “just because a clinical trial shows that three drugs work better than two, it doesn’t mean that every time I have a patient who is eligible I’m going to go with all three.”
It may be that a patient can start on two, with a third added if needed, he added.
“That being said, we want to maximize the synergy of those three, especially in high-risk patients,” he said.
Prior to 2016, popular regimens included CyBorD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone), which were commonly used worldwide. CTD (cyclophosphamide, thalidomide, dexamethasone) was used in Brazil and other countries where it was difficult to obtain bortezomib; VRD was “king of the hill” in the United States, and transplant was routinely recommended, Dr. Mikhael said.
A number of recent studies are changing that paradigm, he said.
One such study, the prospective randomized Intergroupe Francophone du Myélome (IFM) 2013-04 trial, showed that VTD is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) for induction in patients with de novo multiple myeloma. VGPR and PR rates were significantly superior in the VTD arm.
Of note, hematologic toxicity increased in the VCD arm, and the peripheral neuropathy rate was higher in the VTD arm. However, the study was conducted at a time when bortezomib was generally used twice weekly; now it is standard to use it once weekly and subcutaneously, which significantly reduces the risk of peripheral neuropathy.
The authors advocated the preferential use of VTD over VCD for induction, based on the synergistic effect of a proteasome inhibitor and immunomodulatory drug, Dr. Mikhael said.
“Meanwhile, back in the United States, many trials were starting to be built with VRD,” he said, noting that “really extraordinary” responses were seen in phase I and phase II studies.
Perhaps the VRD study (called RVD in this case) that is most cited is the phase III IFM 2009 study comparing RVD with and without autologous stem cell transplant in newly diagnosed younger multiple myeloma patients. Although final results are still pending, interim results reported at the American Society of Hematology 2015 meeting (abstract 391) have been very helpful, Dr. Mikhael said.
The authors reported a 31% reduction in the risk of progression or death with autologous stem cell transplant versus RVD alone in patients with newly diagnosed multiple myeloma, as well as improved rates of thrombotic thrombocytopenic purpura (TTP) and minimal residual disease negativity (MRD). Mortality rates were similar.
The findings show that transplantation is feasible (93%), and associated with acceptable mortality (1.4%), an increased rate of negative MRD versus with RVD alone (80% vs. 65%), an improved 4-year progression-free survival (47% vs. 35%), and improved 4-year TTP (49% vs. 35%).
“Here the question was not so much is RVD the standard ... but is RVD plus transplant superior to RVD alone,” he said.
Surprising to many, especially the “dissenters in the crowd” who thought perhaps RVD would be the death knell to autologous stem cell transplant, transplant actually significantly improved the depth of response, he added.
Median progression-free survival at 10 months was 43% with versus 34% without transplantation.
“So there was definitely an argument here that transplant remains the standard of care,” he said, noting that transplant should be considered as decisions are made about up-front therapy.
As for the trend of bringing carfilzomib in earlier on in treatment, a number of studies, including the phase II CYKLONE study by Dr. Mikhael and his colleagues, suggest it improves the rates of deep response; some show that is especially true when used with transplant.
One study looking at KRD showed that the regimen provides high rates of deep and durable responses with acceptable tolerability – a finding that needs confirmation in a randomized setting.
Other studies are comparing KRD and VRD, and KRD and KCyd (carfilzomib, cyclophosphamide), as well as adding monoclonal antibodies such as daratumumab to treatment regimens, and results are very much anticipated, Dr. Mikhael said.
Currently, however, VRD remains the standard of care in standard risk and intermediate risk patients.
“But consideration in the highest-risk patients should be given to something like KRD,” he said. “We still recommend transplant across the board, we still recommend some form of maintenance therapy, be it with lenalidomide for most patients, but potentially bortezomib combined with carfilzomib in the highest risk patients.”
Dr. Mikhael reported consulting for Abbvie, Celgene, Onyx, and Sanofi.
EXPERT ANALYSIS FROM LYMPHOMA & MYELOMA
Why CLL may go chemo free
NEW YORK – The approach to treating chronic lymphocytic leukemia (CLL) is evolving, and while chemoimmunotherapy remains a reasonable initial option in some cases, a “chemo-free” approach is also a very real possibility, according to Bruce D. Cheson, MD.
A number of studies showing survival benefits with targeted therapies vs. chemoimmunotherapy (CIT) regimens have been completed, including studies that look specifically at outcomes by mutation status and other factors. One example – a likely game changer – is the ALLIANCE trial, a randomized phase III study of bendamustine plus rituximab vs. ibrutinib plus rituximab vs. ibrutinib alone in untreated CLL patients aged 65 years or older, Dr. Cheson of Georgetown University Hospital, Washington, said at an international congress on hematologic malignancies.
“I think [the ALLIANCE] trial has the possibility of totally changing how we treat patients with CLL, even though it was done in older patients,” he said, noting that the study is completed, but final results are pending adequate follow-up.
Based on the available data, he suggests a treatment paradigm for untreated CLL patients who require therapy that begins with consideration of patient age, comorbidities, functional status, and fluorescence in situ hybridization (FISH).
While clinical trial enrollment is preferable, those who are CIT eligible based on age and comorbidities can be treated with bendamustine/rituximab (BR), fludarabine/cyclophosphamide/rituximab (FCR), or ibrutinib.
“I think BR and FCR are both reasonable options, although the latter primarily for young, IGHV-mutated patients, and certainly ibrutinib remains an option for this patient population,” he said.
For those not eligible for CIT, options include ibrutinib and chlorambucil/obinutuzumab. For those with deletion 17p, ibrutinib is the standard for frontline therapy. And for those who are frail, ibrutinib is a good option.
“Some might use an anti-CD20, but as a single agent, it’s not what I would prefer,” Dr. Cheson said, explaining that response rates with such agents are low and tend to lack durability.
CIT remains a reasonable initial option for those patients who are mutated, but with the prolonged progression-free survival seen with ibrutinib in several trials, he predicted that will change over time.
“The role of targeted approaches is a subject of discussion. It takes the most time in my clinic of any discussion I have. [Patients ask] ‘Should I get ibrutinib? Should I get chemoimmunotherapy?’ ” he said. “One needs to take into account patient age and comorbidities, the fact that with CIT you are six [treatments] and done vs. indefinite therapy [with ibrutinib]. There is cost and there is compliance that one needs to consider.”
As for relapsed/refractory CLL, the role of CIT is particularly diminished in the wake of trials such as HELIOS and RESONATE, showing survival benefits with ibrutinib, others showing survival benefits with rituximab/idelalisib (R-idelalisib), and trials showing better results with venetoclax non-CIT regimens than would be expected with CIT regimens. As with treatment-naive CLL patients, age, comorbidities, functional status, and FISH should be considered in those with previously treated CLL who require therapy, and if clinical trial enrollment is not possible, treatment options depend on certain patient characteristics.
“For patients who had a long first response to chemoimmunotherapy, I would still use ibrutinib, and in select patients, R-idelalisib,” he said.
If they had a long response with BR, or FCR, retreatment with those can be considered as well, he noted, adding, “But I don’t see the point when the results with kinase inhibitors are at least as good as, if not better than one would expect with CIT in this context.”
In patients who had short first response, ibrutinib and R-idelalisib are the best options. For those with deletion 17p, the best options are ibrutinib or venetoclax, and possibly R-idelalisib. For frail patients, options include ibrutinib, R-idelalisib, or anti-CD20, although, as with untreated patients, the latter is his least favorite option because of the increased risk of toxicity in this population, he said.
“I think the role of chemoimmunotherapy in CLL is vanishing, and a chemo-free world for CLL patients is a reality,” he said.
Dr. Cheson reported consulting for Acerta, Celgene Pharmacyclics, and Roche-Genentech.
NEW YORK – The approach to treating chronic lymphocytic leukemia (CLL) is evolving, and while chemoimmunotherapy remains a reasonable initial option in some cases, a “chemo-free” approach is also a very real possibility, according to Bruce D. Cheson, MD.
A number of studies showing survival benefits with targeted therapies vs. chemoimmunotherapy (CIT) regimens have been completed, including studies that look specifically at outcomes by mutation status and other factors. One example – a likely game changer – is the ALLIANCE trial, a randomized phase III study of bendamustine plus rituximab vs. ibrutinib plus rituximab vs. ibrutinib alone in untreated CLL patients aged 65 years or older, Dr. Cheson of Georgetown University Hospital, Washington, said at an international congress on hematologic malignancies.
“I think [the ALLIANCE] trial has the possibility of totally changing how we treat patients with CLL, even though it was done in older patients,” he said, noting that the study is completed, but final results are pending adequate follow-up.
Based on the available data, he suggests a treatment paradigm for untreated CLL patients who require therapy that begins with consideration of patient age, comorbidities, functional status, and fluorescence in situ hybridization (FISH).
While clinical trial enrollment is preferable, those who are CIT eligible based on age and comorbidities can be treated with bendamustine/rituximab (BR), fludarabine/cyclophosphamide/rituximab (FCR), or ibrutinib.
“I think BR and FCR are both reasonable options, although the latter primarily for young, IGHV-mutated patients, and certainly ibrutinib remains an option for this patient population,” he said.
For those not eligible for CIT, options include ibrutinib and chlorambucil/obinutuzumab. For those with deletion 17p, ibrutinib is the standard for frontline therapy. And for those who are frail, ibrutinib is a good option.
“Some might use an anti-CD20, but as a single agent, it’s not what I would prefer,” Dr. Cheson said, explaining that response rates with such agents are low and tend to lack durability.
CIT remains a reasonable initial option for those patients who are mutated, but with the prolonged progression-free survival seen with ibrutinib in several trials, he predicted that will change over time.
“The role of targeted approaches is a subject of discussion. It takes the most time in my clinic of any discussion I have. [Patients ask] ‘Should I get ibrutinib? Should I get chemoimmunotherapy?’ ” he said. “One needs to take into account patient age and comorbidities, the fact that with CIT you are six [treatments] and done vs. indefinite therapy [with ibrutinib]. There is cost and there is compliance that one needs to consider.”
As for relapsed/refractory CLL, the role of CIT is particularly diminished in the wake of trials such as HELIOS and RESONATE, showing survival benefits with ibrutinib, others showing survival benefits with rituximab/idelalisib (R-idelalisib), and trials showing better results with venetoclax non-CIT regimens than would be expected with CIT regimens. As with treatment-naive CLL patients, age, comorbidities, functional status, and FISH should be considered in those with previously treated CLL who require therapy, and if clinical trial enrollment is not possible, treatment options depend on certain patient characteristics.
“For patients who had a long first response to chemoimmunotherapy, I would still use ibrutinib, and in select patients, R-idelalisib,” he said.
If they had a long response with BR, or FCR, retreatment with those can be considered as well, he noted, adding, “But I don’t see the point when the results with kinase inhibitors are at least as good as, if not better than one would expect with CIT in this context.”
In patients who had short first response, ibrutinib and R-idelalisib are the best options. For those with deletion 17p, the best options are ibrutinib or venetoclax, and possibly R-idelalisib. For frail patients, options include ibrutinib, R-idelalisib, or anti-CD20, although, as with untreated patients, the latter is his least favorite option because of the increased risk of toxicity in this population, he said.
“I think the role of chemoimmunotherapy in CLL is vanishing, and a chemo-free world for CLL patients is a reality,” he said.
Dr. Cheson reported consulting for Acerta, Celgene Pharmacyclics, and Roche-Genentech.
NEW YORK – The approach to treating chronic lymphocytic leukemia (CLL) is evolving, and while chemoimmunotherapy remains a reasonable initial option in some cases, a “chemo-free” approach is also a very real possibility, according to Bruce D. Cheson, MD.
A number of studies showing survival benefits with targeted therapies vs. chemoimmunotherapy (CIT) regimens have been completed, including studies that look specifically at outcomes by mutation status and other factors. One example – a likely game changer – is the ALLIANCE trial, a randomized phase III study of bendamustine plus rituximab vs. ibrutinib plus rituximab vs. ibrutinib alone in untreated CLL patients aged 65 years or older, Dr. Cheson of Georgetown University Hospital, Washington, said at an international congress on hematologic malignancies.
“I think [the ALLIANCE] trial has the possibility of totally changing how we treat patients with CLL, even though it was done in older patients,” he said, noting that the study is completed, but final results are pending adequate follow-up.
Based on the available data, he suggests a treatment paradigm for untreated CLL patients who require therapy that begins with consideration of patient age, comorbidities, functional status, and fluorescence in situ hybridization (FISH).
While clinical trial enrollment is preferable, those who are CIT eligible based on age and comorbidities can be treated with bendamustine/rituximab (BR), fludarabine/cyclophosphamide/rituximab (FCR), or ibrutinib.
“I think BR and FCR are both reasonable options, although the latter primarily for young, IGHV-mutated patients, and certainly ibrutinib remains an option for this patient population,” he said.
For those not eligible for CIT, options include ibrutinib and chlorambucil/obinutuzumab. For those with deletion 17p, ibrutinib is the standard for frontline therapy. And for those who are frail, ibrutinib is a good option.
“Some might use an anti-CD20, but as a single agent, it’s not what I would prefer,” Dr. Cheson said, explaining that response rates with such agents are low and tend to lack durability.
CIT remains a reasonable initial option for those patients who are mutated, but with the prolonged progression-free survival seen with ibrutinib in several trials, he predicted that will change over time.
“The role of targeted approaches is a subject of discussion. It takes the most time in my clinic of any discussion I have. [Patients ask] ‘Should I get ibrutinib? Should I get chemoimmunotherapy?’ ” he said. “One needs to take into account patient age and comorbidities, the fact that with CIT you are six [treatments] and done vs. indefinite therapy [with ibrutinib]. There is cost and there is compliance that one needs to consider.”
As for relapsed/refractory CLL, the role of CIT is particularly diminished in the wake of trials such as HELIOS and RESONATE, showing survival benefits with ibrutinib, others showing survival benefits with rituximab/idelalisib (R-idelalisib), and trials showing better results with venetoclax non-CIT regimens than would be expected with CIT regimens. As with treatment-naive CLL patients, age, comorbidities, functional status, and FISH should be considered in those with previously treated CLL who require therapy, and if clinical trial enrollment is not possible, treatment options depend on certain patient characteristics.
“For patients who had a long first response to chemoimmunotherapy, I would still use ibrutinib, and in select patients, R-idelalisib,” he said.
If they had a long response with BR, or FCR, retreatment with those can be considered as well, he noted, adding, “But I don’t see the point when the results with kinase inhibitors are at least as good as, if not better than one would expect with CIT in this context.”
In patients who had short first response, ibrutinib and R-idelalisib are the best options. For those with deletion 17p, the best options are ibrutinib or venetoclax, and possibly R-idelalisib. For frail patients, options include ibrutinib, R-idelalisib, or anti-CD20, although, as with untreated patients, the latter is his least favorite option because of the increased risk of toxicity in this population, he said.
“I think the role of chemoimmunotherapy in CLL is vanishing, and a chemo-free world for CLL patients is a reality,” he said.
Dr. Cheson reported consulting for Acerta, Celgene Pharmacyclics, and Roche-Genentech.
Idelalisib held unlikely to become frontline therapy for CLL
NEW YORK – Safety issues with idelalisib, a first-in-class PI3K delta inhibitor, are an important concern in patients with chronic lymphocytic leukemia – particularly those aged 65 years and younger, according to Steven Coutre, MD.
Findings from the second interim analysis of the pivotal trial for idelalisib as reported at the 2014 annual meeting of the American Society of Hematology (Sharman J., et al. Abstract 330) and a recent update from an open-label extension represent the longest reported follow-up of idelalisib-treated patients to date. Those analyses showed substantial progression-free and overall survival advantages with idelalisib plus rituximab vs. placebo plus rituximab (progression-free survival in the latest update was 19.4 vs. 7.3 months, respectively; hazard ratio 0.25), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.
“Still, even with that report, the follow-up on that initial study was relatively short, and I think it really underreports some of the safety issues of the toxicities that we see,” he said at an international congress on hematologic malignancies.
To further investigate those safety issues, Dr. Coutre and his colleagues performed an integrated analysis of eight clinical trials, including the pivotal trial. That analysis found idelalisib to be efficacious, but significant toxicities were noted, “particularly in younger less heavily-pretreated patients. [Idelalisib] should not be used as frontline therapy ... and I don’t think it will be developed in the future as frontline therapy,” Dr. Coutre said.
“At least in the relapse setting, idelalisib plus rituximab is a choice for all of our patients, but it has to be a considered choice; you have to put it in the context of other therapies that the patients have available to them and make a decision based on your individual patient.”
In the analysis, Dr. Coutre and his colleagues found numerous adverse events occurring in 15% or more of idelalisib-treated patients. These included diarrhea/colitis – with median onset at 7.1 months – in 37% who received monotherapy and 40% who received combination therapy (grade 3 or greater diarrhea/colitis in 11% and 17%, respectively), and pneumonia in 13% and 18% of patients (grade 3 or greater in 11% and 14%, respectively), Dr. Coutre said.
Transaminitis – which was observed early in the studies, usually within the first 8 weeks of treatment – also was common, occurring in 50% and 47% of those with monotherapy and combination therapy, respectively (grade 3 or greater, 16% and 13%, respectively).
Pneumonitis occurred in about 3% of patients, and usually within the first 6 months of therapy.
“So that’s sort of where things were until earlier this year when we learned from several ongoing studies, very important studies in both previously treated patients with low-grade lymphomas and previously untreated patients, that there was a further problem – and that is a difference in mortality,” he said.
Patients in many of these studies, including all of those where it was being used for previously untreated patients, were taken off the drug because of this finding.
“As a result of further analysis of these studies, there’s a new safety label indication,” he said.
Of note, in another idelalisib study reported at ASH 2015 an age-related toxicity concern emerged.
“Idelalisib was used for previously untreated patients. But the distinction here is that for the first time it was being used in younger patients – patients under the age of 65,” he said, noting that severe transaminitis occurred in a significant number of the younger patients.
More than half (52%) of patients had grade 3 or greater hepatotoxicity and all 7 subjects aged 65 years and younger required systemic steroids for toxicities.
Age was found in the study to be a significant risk factor for early hepatotoxicity.
“We’re finally starting to understand the mechanisms behind this, or at least the likely mechanisms, and this seems to be immune mediated,” he said, adding, “you see a lymphocytic infiltrate on liver biopsies, you see a lymphocytic colitis in patients who receive idelalisib.”
Typically, toxicities in these patients can be managed with corticosteroids, but in some cases of severe toxicity even steroids seem to be insufficient, he said.
Further, rapid recurrence is often seen upon re-exposure to the drug, especially with respect to hepatotoxicity, he added.
Preclinical data from mouse models supports this mechanism.
“And importantly [those models] demonstrated a decrease in regulatory T cells in patients treated with idelalisib,” he said.
Dr. Coutre reported consulting for Abbvie, Celgene, Gilead, Janssen, and Pharmacyclics.
NEW YORK – Safety issues with idelalisib, a first-in-class PI3K delta inhibitor, are an important concern in patients with chronic lymphocytic leukemia – particularly those aged 65 years and younger, according to Steven Coutre, MD.
Findings from the second interim analysis of the pivotal trial for idelalisib as reported at the 2014 annual meeting of the American Society of Hematology (Sharman J., et al. Abstract 330) and a recent update from an open-label extension represent the longest reported follow-up of idelalisib-treated patients to date. Those analyses showed substantial progression-free and overall survival advantages with idelalisib plus rituximab vs. placebo plus rituximab (progression-free survival in the latest update was 19.4 vs. 7.3 months, respectively; hazard ratio 0.25), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.
“Still, even with that report, the follow-up on that initial study was relatively short, and I think it really underreports some of the safety issues of the toxicities that we see,” he said at an international congress on hematologic malignancies.
To further investigate those safety issues, Dr. Coutre and his colleagues performed an integrated analysis of eight clinical trials, including the pivotal trial. That analysis found idelalisib to be efficacious, but significant toxicities were noted, “particularly in younger less heavily-pretreated patients. [Idelalisib] should not be used as frontline therapy ... and I don’t think it will be developed in the future as frontline therapy,” Dr. Coutre said.
“At least in the relapse setting, idelalisib plus rituximab is a choice for all of our patients, but it has to be a considered choice; you have to put it in the context of other therapies that the patients have available to them and make a decision based on your individual patient.”
In the analysis, Dr. Coutre and his colleagues found numerous adverse events occurring in 15% or more of idelalisib-treated patients. These included diarrhea/colitis – with median onset at 7.1 months – in 37% who received monotherapy and 40% who received combination therapy (grade 3 or greater diarrhea/colitis in 11% and 17%, respectively), and pneumonia in 13% and 18% of patients (grade 3 or greater in 11% and 14%, respectively), Dr. Coutre said.
Transaminitis – which was observed early in the studies, usually within the first 8 weeks of treatment – also was common, occurring in 50% and 47% of those with monotherapy and combination therapy, respectively (grade 3 or greater, 16% and 13%, respectively).
Pneumonitis occurred in about 3% of patients, and usually within the first 6 months of therapy.
“So that’s sort of where things were until earlier this year when we learned from several ongoing studies, very important studies in both previously treated patients with low-grade lymphomas and previously untreated patients, that there was a further problem – and that is a difference in mortality,” he said.
Patients in many of these studies, including all of those where it was being used for previously untreated patients, were taken off the drug because of this finding.
“As a result of further analysis of these studies, there’s a new safety label indication,” he said.
Of note, in another idelalisib study reported at ASH 2015 an age-related toxicity concern emerged.
“Idelalisib was used for previously untreated patients. But the distinction here is that for the first time it was being used in younger patients – patients under the age of 65,” he said, noting that severe transaminitis occurred in a significant number of the younger patients.
More than half (52%) of patients had grade 3 or greater hepatotoxicity and all 7 subjects aged 65 years and younger required systemic steroids for toxicities.
Age was found in the study to be a significant risk factor for early hepatotoxicity.
“We’re finally starting to understand the mechanisms behind this, or at least the likely mechanisms, and this seems to be immune mediated,” he said, adding, “you see a lymphocytic infiltrate on liver biopsies, you see a lymphocytic colitis in patients who receive idelalisib.”
Typically, toxicities in these patients can be managed with corticosteroids, but in some cases of severe toxicity even steroids seem to be insufficient, he said.
Further, rapid recurrence is often seen upon re-exposure to the drug, especially with respect to hepatotoxicity, he added.
Preclinical data from mouse models supports this mechanism.
“And importantly [those models] demonstrated a decrease in regulatory T cells in patients treated with idelalisib,” he said.
Dr. Coutre reported consulting for Abbvie, Celgene, Gilead, Janssen, and Pharmacyclics.
NEW YORK – Safety issues with idelalisib, a first-in-class PI3K delta inhibitor, are an important concern in patients with chronic lymphocytic leukemia – particularly those aged 65 years and younger, according to Steven Coutre, MD.
Findings from the second interim analysis of the pivotal trial for idelalisib as reported at the 2014 annual meeting of the American Society of Hematology (Sharman J., et al. Abstract 330) and a recent update from an open-label extension represent the longest reported follow-up of idelalisib-treated patients to date. Those analyses showed substantial progression-free and overall survival advantages with idelalisib plus rituximab vs. placebo plus rituximab (progression-free survival in the latest update was 19.4 vs. 7.3 months, respectively; hazard ratio 0.25), said Dr. Coutre, professor of medicine at Stanford (Calif.) University.
“Still, even with that report, the follow-up on that initial study was relatively short, and I think it really underreports some of the safety issues of the toxicities that we see,” he said at an international congress on hematologic malignancies.
To further investigate those safety issues, Dr. Coutre and his colleagues performed an integrated analysis of eight clinical trials, including the pivotal trial. That analysis found idelalisib to be efficacious, but significant toxicities were noted, “particularly in younger less heavily-pretreated patients. [Idelalisib] should not be used as frontline therapy ... and I don’t think it will be developed in the future as frontline therapy,” Dr. Coutre said.
“At least in the relapse setting, idelalisib plus rituximab is a choice for all of our patients, but it has to be a considered choice; you have to put it in the context of other therapies that the patients have available to them and make a decision based on your individual patient.”
In the analysis, Dr. Coutre and his colleagues found numerous adverse events occurring in 15% or more of idelalisib-treated patients. These included diarrhea/colitis – with median onset at 7.1 months – in 37% who received monotherapy and 40% who received combination therapy (grade 3 or greater diarrhea/colitis in 11% and 17%, respectively), and pneumonia in 13% and 18% of patients (grade 3 or greater in 11% and 14%, respectively), Dr. Coutre said.
Transaminitis – which was observed early in the studies, usually within the first 8 weeks of treatment – also was common, occurring in 50% and 47% of those with monotherapy and combination therapy, respectively (grade 3 or greater, 16% and 13%, respectively).
Pneumonitis occurred in about 3% of patients, and usually within the first 6 months of therapy.
“So that’s sort of where things were until earlier this year when we learned from several ongoing studies, very important studies in both previously treated patients with low-grade lymphomas and previously untreated patients, that there was a further problem – and that is a difference in mortality,” he said.
Patients in many of these studies, including all of those where it was being used for previously untreated patients, were taken off the drug because of this finding.
“As a result of further analysis of these studies, there’s a new safety label indication,” he said.
Of note, in another idelalisib study reported at ASH 2015 an age-related toxicity concern emerged.
“Idelalisib was used for previously untreated patients. But the distinction here is that for the first time it was being used in younger patients – patients under the age of 65,” he said, noting that severe transaminitis occurred in a significant number of the younger patients.
More than half (52%) of patients had grade 3 or greater hepatotoxicity and all 7 subjects aged 65 years and younger required systemic steroids for toxicities.
Age was found in the study to be a significant risk factor for early hepatotoxicity.
“We’re finally starting to understand the mechanisms behind this, or at least the likely mechanisms, and this seems to be immune mediated,” he said, adding, “you see a lymphocytic infiltrate on liver biopsies, you see a lymphocytic colitis in patients who receive idelalisib.”
Typically, toxicities in these patients can be managed with corticosteroids, but in some cases of severe toxicity even steroids seem to be insufficient, he said.
Further, rapid recurrence is often seen upon re-exposure to the drug, especially with respect to hepatotoxicity, he added.
Preclinical data from mouse models supports this mechanism.
“And importantly [those models] demonstrated a decrease in regulatory T cells in patients treated with idelalisib,” he said.
Dr. Coutre reported consulting for Abbvie, Celgene, Gilead, Janssen, and Pharmacyclics.
EXPERT ANALYSIS FROM LYMPHOMA & MYELOMA
Combine flow and HTS for sensitive MRD detection in CLL, speaker says
laser beam
Photo courtesy of NIH
NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.
The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.
“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”
Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.
In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.
History of MRD analysis
The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10-4) leukocytes, regardless of the tissue used.
Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.
Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.
“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.
Technologies
Several technologies can be used to assess MRD.
Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.
Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.
“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.
HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.
Flow cytometry and HTS
A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.
According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10-4).
Assays had to be independent and compatible with older, established therapies as well as newer treatments.
For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).
Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.
And while PCR is more sensitive than flow cytometry (sensitive to 10-5 to 10-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.
The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials.
They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.
The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10-4) level.
Peripheral blood or bone marrow?
“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”
Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.
Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the bone marrow (PB-/BM-) (Rawstron abstract S794).
But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.
And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.
“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.
Prognostic value of MRD assessment
Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.
And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.
Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.
In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).
“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.
Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.
And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.
In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.
For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.
“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.” 
laser beam
Photo courtesy of NIH
NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.
The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.
“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”
Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.
In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.
History of MRD analysis
The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10-4) leukocytes, regardless of the tissue used.
Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.
Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.
“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.
Technologies
Several technologies can be used to assess MRD.
Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.
Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.
“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.
HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.
Flow cytometry and HTS
A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.
According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10-4).
Assays had to be independent and compatible with older, established therapies as well as newer treatments.
For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).
Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.
And while PCR is more sensitive than flow cytometry (sensitive to 10-5 to 10-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.
The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials.
They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.
The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10-4) level.
Peripheral blood or bone marrow?
“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”
Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.
Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the bone marrow (PB-/BM-) (Rawstron abstract S794).
But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.
And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.
“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.
Prognostic value of MRD assessment
Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.
And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.
Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.
In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).
“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.
Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.
And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.
In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.
For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.
“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”
laser beam
Photo courtesy of NIH
NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.
The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.
“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”
Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.
In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.
History of MRD analysis
The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10-4) leukocytes, regardless of the tissue used.
Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.
Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.
“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.
Technologies
Several technologies can be used to assess MRD.
Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.
Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.
“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.
HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.
Flow cytometry and HTS
A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.
According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10-4).
Assays had to be independent and compatible with older, established therapies as well as newer treatments.
For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).
Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.
And while PCR is more sensitive than flow cytometry (sensitive to 10-5 to 10-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.
The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials.
They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.
The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10-4) level.
Peripheral blood or bone marrow?
“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”
Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.
Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the bone marrow (PB-/BM-) (Rawstron abstract S794).
But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.
And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.
“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.
Prognostic value of MRD assessment
Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.
And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.
Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.
In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).
“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.
Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.
And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.
In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.
For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.
“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”
Rethinking testing in multiple myeloma
NEW YORK—As the number of therapeutic options for multiple myeloma (MM) increases, so too does the need to reassess prognostic markers for the disease, according to a speaker at Lymphoma & Myeloma 2016.
“A good prognosticator for one patient may have little meaning for another patient,” said Scott Ely, MD, of Weill Cornell Medicine in New York, New York.
“It’s really important before doing any testing to ask, ‘Will the result of this test affect patient care?’”
To answer this question, Dr Ely reviewed the different testing methods used in MM patients and explained the advantages of each.
“[I]t’s really important to understand that a lot of methods are really great for research but don’t work or are not feasible for real-life diagnostic purposes,” he added.
Dr Ely also said it’s important to consider who wants the data, how much the test costs, and who will pay for it, keeping in mind that, these days, the patient’s share of the bill is increasing.
Dr Ely stressed that, until more precise targets or a better understanding of drug mechanisms exist, clinical features—patient age, performance status or frailty, renal function, and disease stage—remain the most important prognosticators.
“But still, 2 patients in the same box based on clinical features will often have very different outcomes,” he said. “So in addition to clinical factors, we need prognosticators for tumor cell behavior. We need to know how fast they are growing and how they will respond to treatment.”
Methods to assess myeloma cell proliferation
Cytogenetics (FISH), gene array technology, and genomics using next-generation sequencing can provide some information, but they are not necessarily good methods to assess proliferation, Dr Ely explained.
To determine the proliferation rate of a patient’s cancer, you can look at tens of thousands of genes by gene array, he said, “or you can just look at one thing, which is Ki67.”
If the cell has Ki67, it’s proliferating, and if it doesn’t have Ki67, it’s not.
“Often, looking at all the other upstream molecules can be confusing and even misleading,” he noted. “So Ki67 is the best way to look for proliferation when it comes to myeloma.”
Other methods include the plasma cell labeling index (PCLI), gene expression profiling, flow cytometry, and multiplex immunohistochemistry (mIHC).
Dr Ely, as a hematopathologist, has found IHC to be the best method to determine proliferation, most likely because the other methods use bone marrow aspirate and IHC uses core biopsy of histologic sections.
It’s the gold standard, he said, for determining the percentage of plasma cells because core biopsy takes a “complete, intact piece of marrow that’s truly representative of what’s going on in the patient.”
In a study of more than 350 bone marrow samples comparing core biopsy with aspirate smears, plasma cells were under-represented in approximately half the aspirate specimens by about 20%.
In addition, Dr Ely noted that myeloma cells die very quickly once they are removed from the stroma.
“So if you take myeloma cells out as an aspirate,” he said, “myeloma cells die and others survive.”
And if the aspirate is sent overnight to the lab, the number of plasma cells in the specimen will already be reduced when the lab gets it.
Aspirates are best for leukemia and myelodysplastic syndromes, Dr Ely said, while core biopsies are best for lymphoma and myeloma.
Plasma cell proliferation indices
Proliferation is a myeloma-defining criterion, Dr Ely said. It predicts an 80% probability of progression in 2 years.
And PCLI has shown conclusively that plasma cell proliferation is a good prognosticator in all types of myeloma patients. However, it is not really feasible to use or easy to perform.
On the other hand, core biopsy combined with IHC is a feasible way of measuring plasma cell proliferation for routine clinical use.
Using standard IHC, it’s difficult to distinguish proliferating from non-proliferating cells, Dr Ely said.
“The solution to this problem is multiplex IHC,” he said, using 3 stains—red for CD138 (the plasma cell marker), brown for Ki67 (the proliferation marker), and blue as a negative nuclear counter stain.
A red membrane around the stained cell indicates a myeloma cell. Non-proliferating MM cells have blue nuclei, and proliferating MM cells have brown nuclei.
This assay is called the plasma cell proliferation index (PCPI).
“[A]ny lab that can do standard IHC can do multiplex IHC,” Dr Ely added.
It uses the same machines, the same reagents, the same expertise, and it’s easy to set up.
Validation studies
Dr Ely and his colleagues performed extensive laboratory validation to make sure the new PCPI correlated with the old PCLI.
They also performed 3 clinical validation studies, the first in bone marrow transplant patients. The investigators followed the patients for 12 years and found the PCPI correlated with survival.
The investigators performed a second clinical validation in 151 newly diagnosed patients. On multivariate analysis, the team found PCPI to be an independent prognostic indicator.
Each 1% increase in PCPI was associated with a 3% increased risk of disease progression (hazard ratio=1.03, 95% CI, 1.01-1.05, P=0.02).
The third clinical validation the investigators conducted was a retrospective cohort study in which they evaluated the effect of rising PCPI at relapse in 37 patients. The team defined rising PCPI as a 5% or greater increase in plasma cells.
Nineteen patients had a rising PCPI, and 17 patients had stable or decreased PCPI.
Patients with a rising PCPI at relapse had a shorter median overall survival than patients with stable or decreased PCPI—72 months and not reached, respectively (P=0.0069).
Patients with a rising PCPI also had a shorter median progression-free survival on first post-relapse treatment compared to patients with stable or decreased PCPI—25 months and 47 months, respectively (P=0.036).
“It’s also important to note that if you’re getting high-risk by PCPI plus β2-microglobulin albumin, I’d advise that, for all high-risk patients, getting the cytogenetics doesn’t really help,” Dr Ely said
Three patients considered high-risk by cytogenetics were standard-risk by PCPI plus β2 microglobulin.
“So we found that cytogenetics isn’t really adding anything except the cost,” Dr Ely asserted.
Other labs are now using PCPI for prognostication, he noted, adding, “We hope PCPI will be incorporated into the International Myeloma Working Group diagnosis of MM.”
NEW YORK—As the number of therapeutic options for multiple myeloma (MM) increases, so too does the need to reassess prognostic markers for the disease, according to a speaker at Lymphoma & Myeloma 2016.
“A good prognosticator for one patient may have little meaning for another patient,” said Scott Ely, MD, of Weill Cornell Medicine in New York, New York.
“It’s really important before doing any testing to ask, ‘Will the result of this test affect patient care?’”
To answer this question, Dr Ely reviewed the different testing methods used in MM patients and explained the advantages of each.
“[I]t’s really important to understand that a lot of methods are really great for research but don’t work or are not feasible for real-life diagnostic purposes,” he added.
Dr Ely also said it’s important to consider who wants the data, how much the test costs, and who will pay for it, keeping in mind that, these days, the patient’s share of the bill is increasing.
Dr Ely stressed that, until more precise targets or a better understanding of drug mechanisms exist, clinical features—patient age, performance status or frailty, renal function, and disease stage—remain the most important prognosticators.
“But still, 2 patients in the same box based on clinical features will often have very different outcomes,” he said. “So in addition to clinical factors, we need prognosticators for tumor cell behavior. We need to know how fast they are growing and how they will respond to treatment.”
Methods to assess myeloma cell proliferation
Cytogenetics (FISH), gene array technology, and genomics using next-generation sequencing can provide some information, but they are not necessarily good methods to assess proliferation, Dr Ely explained.
To determine the proliferation rate of a patient’s cancer, you can look at tens of thousands of genes by gene array, he said, “or you can just look at one thing, which is Ki67.”
If the cell has Ki67, it’s proliferating, and if it doesn’t have Ki67, it’s not.
“Often, looking at all the other upstream molecules can be confusing and even misleading,” he noted. “So Ki67 is the best way to look for proliferation when it comes to myeloma.”
Other methods include the plasma cell labeling index (PCLI), gene expression profiling, flow cytometry, and multiplex immunohistochemistry (mIHC).
Dr Ely, as a hematopathologist, has found IHC to be the best method to determine proliferation, most likely because the other methods use bone marrow aspirate and IHC uses core biopsy of histologic sections.
It’s the gold standard, he said, for determining the percentage of plasma cells because core biopsy takes a “complete, intact piece of marrow that’s truly representative of what’s going on in the patient.”
In a study of more than 350 bone marrow samples comparing core biopsy with aspirate smears, plasma cells were under-represented in approximately half the aspirate specimens by about 20%.
In addition, Dr Ely noted that myeloma cells die very quickly once they are removed from the stroma.
“So if you take myeloma cells out as an aspirate,” he said, “myeloma cells die and others survive.”
And if the aspirate is sent overnight to the lab, the number of plasma cells in the specimen will already be reduced when the lab gets it.
Aspirates are best for leukemia and myelodysplastic syndromes, Dr Ely said, while core biopsies are best for lymphoma and myeloma.
Plasma cell proliferation indices
Proliferation is a myeloma-defining criterion, Dr Ely said. It predicts an 80% probability of progression in 2 years.
And PCLI has shown conclusively that plasma cell proliferation is a good prognosticator in all types of myeloma patients. However, it is not really feasible to use or easy to perform.
On the other hand, core biopsy combined with IHC is a feasible way of measuring plasma cell proliferation for routine clinical use.
Using standard IHC, it’s difficult to distinguish proliferating from non-proliferating cells, Dr Ely said.
“The solution to this problem is multiplex IHC,” he said, using 3 stains—red for CD138 (the plasma cell marker), brown for Ki67 (the proliferation marker), and blue as a negative nuclear counter stain.
A red membrane around the stained cell indicates a myeloma cell. Non-proliferating MM cells have blue nuclei, and proliferating MM cells have brown nuclei.
This assay is called the plasma cell proliferation index (PCPI).
“[A]ny lab that can do standard IHC can do multiplex IHC,” Dr Ely added.
It uses the same machines, the same reagents, the same expertise, and it’s easy to set up.
Validation studies
Dr Ely and his colleagues performed extensive laboratory validation to make sure the new PCPI correlated with the old PCLI.
They also performed 3 clinical validation studies, the first in bone marrow transplant patients. The investigators followed the patients for 12 years and found the PCPI correlated with survival.
The investigators performed a second clinical validation in 151 newly diagnosed patients. On multivariate analysis, the team found PCPI to be an independent prognostic indicator.
Each 1% increase in PCPI was associated with a 3% increased risk of disease progression (hazard ratio=1.03, 95% CI, 1.01-1.05, P=0.02).
The third clinical validation the investigators conducted was a retrospective cohort study in which they evaluated the effect of rising PCPI at relapse in 37 patients. The team defined rising PCPI as a 5% or greater increase in plasma cells.
Nineteen patients had a rising PCPI, and 17 patients had stable or decreased PCPI.
Patients with a rising PCPI at relapse had a shorter median overall survival than patients with stable or decreased PCPI—72 months and not reached, respectively (P=0.0069).
Patients with a rising PCPI also had a shorter median progression-free survival on first post-relapse treatment compared to patients with stable or decreased PCPI—25 months and 47 months, respectively (P=0.036).
“It’s also important to note that if you’re getting high-risk by PCPI plus β2-microglobulin albumin, I’d advise that, for all high-risk patients, getting the cytogenetics doesn’t really help,” Dr Ely said
Three patients considered high-risk by cytogenetics were standard-risk by PCPI plus β2 microglobulin.
“So we found that cytogenetics isn’t really adding anything except the cost,” Dr Ely asserted.
Other labs are now using PCPI for prognostication, he noted, adding, “We hope PCPI will be incorporated into the International Myeloma Working Group diagnosis of MM.”
NEW YORK—As the number of therapeutic options for multiple myeloma (MM) increases, so too does the need to reassess prognostic markers for the disease, according to a speaker at Lymphoma & Myeloma 2016.
“A good prognosticator for one patient may have little meaning for another patient,” said Scott Ely, MD, of Weill Cornell Medicine in New York, New York.
“It’s really important before doing any testing to ask, ‘Will the result of this test affect patient care?’”
To answer this question, Dr Ely reviewed the different testing methods used in MM patients and explained the advantages of each.
“[I]t’s really important to understand that a lot of methods are really great for research but don’t work or are not feasible for real-life diagnostic purposes,” he added.
Dr Ely also said it’s important to consider who wants the data, how much the test costs, and who will pay for it, keeping in mind that, these days, the patient’s share of the bill is increasing.
Dr Ely stressed that, until more precise targets or a better understanding of drug mechanisms exist, clinical features—patient age, performance status or frailty, renal function, and disease stage—remain the most important prognosticators.
“But still, 2 patients in the same box based on clinical features will often have very different outcomes,” he said. “So in addition to clinical factors, we need prognosticators for tumor cell behavior. We need to know how fast they are growing and how they will respond to treatment.”
Methods to assess myeloma cell proliferation
Cytogenetics (FISH), gene array technology, and genomics using next-generation sequencing can provide some information, but they are not necessarily good methods to assess proliferation, Dr Ely explained.
To determine the proliferation rate of a patient’s cancer, you can look at tens of thousands of genes by gene array, he said, “or you can just look at one thing, which is Ki67.”
If the cell has Ki67, it’s proliferating, and if it doesn’t have Ki67, it’s not.
“Often, looking at all the other upstream molecules can be confusing and even misleading,” he noted. “So Ki67 is the best way to look for proliferation when it comes to myeloma.”
Other methods include the plasma cell labeling index (PCLI), gene expression profiling, flow cytometry, and multiplex immunohistochemistry (mIHC).
Dr Ely, as a hematopathologist, has found IHC to be the best method to determine proliferation, most likely because the other methods use bone marrow aspirate and IHC uses core biopsy of histologic sections.
It’s the gold standard, he said, for determining the percentage of plasma cells because core biopsy takes a “complete, intact piece of marrow that’s truly representative of what’s going on in the patient.”
In a study of more than 350 bone marrow samples comparing core biopsy with aspirate smears, plasma cells were under-represented in approximately half the aspirate specimens by about 20%.
In addition, Dr Ely noted that myeloma cells die very quickly once they are removed from the stroma.
“So if you take myeloma cells out as an aspirate,” he said, “myeloma cells die and others survive.”
And if the aspirate is sent overnight to the lab, the number of plasma cells in the specimen will already be reduced when the lab gets it.
Aspirates are best for leukemia and myelodysplastic syndromes, Dr Ely said, while core biopsies are best for lymphoma and myeloma.
Plasma cell proliferation indices
Proliferation is a myeloma-defining criterion, Dr Ely said. It predicts an 80% probability of progression in 2 years.
And PCLI has shown conclusively that plasma cell proliferation is a good prognosticator in all types of myeloma patients. However, it is not really feasible to use or easy to perform.
On the other hand, core biopsy combined with IHC is a feasible way of measuring plasma cell proliferation for routine clinical use.
Using standard IHC, it’s difficult to distinguish proliferating from non-proliferating cells, Dr Ely said.
“The solution to this problem is multiplex IHC,” he said, using 3 stains—red for CD138 (the plasma cell marker), brown for Ki67 (the proliferation marker), and blue as a negative nuclear counter stain.
A red membrane around the stained cell indicates a myeloma cell. Non-proliferating MM cells have blue nuclei, and proliferating MM cells have brown nuclei.
This assay is called the plasma cell proliferation index (PCPI).
“[A]ny lab that can do standard IHC can do multiplex IHC,” Dr Ely added.
It uses the same machines, the same reagents, the same expertise, and it’s easy to set up.
Validation studies
Dr Ely and his colleagues performed extensive laboratory validation to make sure the new PCPI correlated with the old PCLI.
They also performed 3 clinical validation studies, the first in bone marrow transplant patients. The investigators followed the patients for 12 years and found the PCPI correlated with survival.
The investigators performed a second clinical validation in 151 newly diagnosed patients. On multivariate analysis, the team found PCPI to be an independent prognostic indicator.
Each 1% increase in PCPI was associated with a 3% increased risk of disease progression (hazard ratio=1.03, 95% CI, 1.01-1.05, P=0.02).
The third clinical validation the investigators conducted was a retrospective cohort study in which they evaluated the effect of rising PCPI at relapse in 37 patients. The team defined rising PCPI as a 5% or greater increase in plasma cells.
Nineteen patients had a rising PCPI, and 17 patients had stable or decreased PCPI.
Patients with a rising PCPI at relapse had a shorter median overall survival than patients with stable or decreased PCPI—72 months and not reached, respectively (P=0.0069).
Patients with a rising PCPI also had a shorter median progression-free survival on first post-relapse treatment compared to patients with stable or decreased PCPI—25 months and 47 months, respectively (P=0.036).
“It’s also important to note that if you’re getting high-risk by PCPI plus β2-microglobulin albumin, I’d advise that, for all high-risk patients, getting the cytogenetics doesn’t really help,” Dr Ely said
Three patients considered high-risk by cytogenetics were standard-risk by PCPI plus β2 microglobulin.
“So we found that cytogenetics isn’t really adding anything except the cost,” Dr Ely asserted.
Other labs are now using PCPI for prognostication, he noted, adding, “We hope PCPI will be incorporated into the International Myeloma Working Group diagnosis of MM.”
Genetic screening for CLL premature, speaker says
Photo courtesy of the
National Institute
of General Medical Science
NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).
First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.
However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.
“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.
“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.
Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.
Demographic risk factors
Dr Slager noted that age, gender, and race are risk factors for CLL.
Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.
There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.
There is a higher incidence of CLL in Caucasians than Asians, for both males and females.
“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”
However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.
Beyond demographic factors
The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.
In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.
The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.
This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.
Medical history
Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.
However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.
The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.
“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.
Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.
Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.
Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.
Occupational exposures
Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.
Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.
Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.
Family history
One of the strongest risk factors for CLL is family history.
Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.
They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).
GWAS in CLL
Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.
Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.
Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.
Unrelated cases and controls are included in the studies.
The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.
In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.
They identified 9 more inherited variances with CLL, for a total of 43 identified to date.
The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.
“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”
Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.
However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.
She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.
Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.
For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.
Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.
Impact on clinical practice
Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.
Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.
MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.
“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”
Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.
“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”
For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”
Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.
Photo courtesy of the
National Institute
of General Medical Science
NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).
First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.
However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.
“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.
“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.
Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.
Demographic risk factors
Dr Slager noted that age, gender, and race are risk factors for CLL.
Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.
There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.
There is a higher incidence of CLL in Caucasians than Asians, for both males and females.
“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”
However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.
Beyond demographic factors
The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.
In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.
The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.
This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.
Medical history
Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.
However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.
The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.
“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.
Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.
Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.
Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.
Occupational exposures
Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.
Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.
Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.
Family history
One of the strongest risk factors for CLL is family history.
Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.
They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).
GWAS in CLL
Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.
Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.
Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.
Unrelated cases and controls are included in the studies.
The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.
In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.
They identified 9 more inherited variances with CLL, for a total of 43 identified to date.
The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.
“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”
Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.
However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.
She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.
Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.
For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.
Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.
Impact on clinical practice
Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.
Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.
MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.
“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”
Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.
“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”
For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”
Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.
Photo courtesy of the
National Institute
of General Medical Science
NEW YORK—Research has shown that family history is a strong risk factor for developing chronic lymphocytic leukemia (CLL).
First-degree relatives have an 8.5-fold risk of getting CLL and an increased risk of other lymphoproliferative disorders, according to a study published in 2009.
However, despite the strong evidence of a genetic contribution, one expert believes it’s premature to bring genetic testing into the clinic for screening in CLL.
“At this time, we do not recommend genetic screening,” said Susan Slager, PhD, of the Mayo Clinic in Rochester, Minnesota.
“There’s no known relationship between the inherited variants and treatment response,” she explained, and the relatively low incidence of CLL argues against active screening in affected families at present.
Dr Slager discussed genetic and non-genetic factors associated with CLL and the clinical implications of these factors at Lymphoma & Myeloma 2016.
Demographic risk factors
Dr Slager noted that age, gender, and race are risk factors for CLL.
Individuals aged 65 to 74 have the highest incidence of CLL, at 28%, while the risk is almost non-existent for those under age 20, she said.
There is a higher incidence of CLL in males than in females, and the reason for this gender disparity is unknown.
There is a higher incidence of CLL in Caucasians than Asians, for both males and females.
“Again, it’s unknown why there’s this variability in incidence in CLL,” Dr Slager said. “Obviously, age, sex, and race—these are things you can’t modify. You’re stuck with them.”
However, several studies have been undertaken to look at some of the potentially modifiable factors associated with CLL.
Beyond demographic factors
The International Lymphoma Epidemiology Consortium, known as InterLymph, was initiated in 2001 to evaluate the association of risk factors in CLL. Study centers are located primarily in North America and Europe, with one in Australia.
In one of the larger InterLymph studies, investigators evaluated risk factors—lifestyle exposure, reproductive history, medical history, occupational exposures, farming exposure, and family history—in 2440 CLL patients and 15,186 controls.
The investigators found that sun exposure and atopy—allergies, asthma, eczema, and hay fever—have a protective effect in CLL, while serological hepatitis C virus (HCV) infections, farming exposure, and family history carry an increased risk of CLL.
This confirmed an earlier study conducted in New South Wales, Australia, that had uncovered an inverse association between sun exposure and non-Hodgkin lymphoma (NHL) risk, which fell significantly with increasing recreational sun exposure.
Medical history
Another earlier study from New South Wales revealed a 20% reduction in the risk of NHL for any specific allergy.
However, the investigators of the large, more recent study observed little to no evidence of reduced risk for asthma and eczema.
The underlying biology for atopy or allergies is a hyper-immune system, Dr Slager explained.
“So if you have a hyper-immune system, then we hypothesize that you have protection against CLL,” she said.
Another medical exposure investigators analyzed that impacts CLL risk is HCV. People infected with HCV have an increased risk of CLL, perhaps due to chronic antigen stimulation or possibly disruption of the T-cell function.
Height is also associated with CLL. CLL risk increases with greater height. The concept is that taller individuals have increased exposure to growth hormones that possibly result in cell proliferation.
Another hypothesis supporting the height association is that people of shorter stature experience more infections, which could result in a stronger immune system. And a stronger immune system perhaps protects against NHL.
Occupational exposures
Investigators consistently observed a 20% increased risk of CLL for people living or working on a farm.
Animal farmers, as opposed to crop farmers, experienced some protection. However, the sample size was too small to be conclusive, with only 29 people across all studies being animal farmers.
Among other occupations evaluated, hairdressers also had an increased risk of CLL, although this too was based on a small sample size.
Family history
One of the strongest risk factors for CLL is family history.
Using population-based registry data from Sweden, investigators found that people with a first-degree relative with CLL have an 8.5-fold risk of CLL.
They also have an elevated risk of other lymphoproliferative disorders, including NHL (1.9-fold risk), Waldenström’s macroglobulinemia (4.0-fold risk), hairy cell leukemia (3.3-fold risk), and follicular lymphoma (1.6-fold risk).
GWAS in CLL
Investigators conducted genome-wide association studies (GWAS) to determine what is driving the familial risk.
Dr Slager described these studies as an agnostic approach that looks across the entire genome to determine which regions are associated with a trait of interest.
Typically, many markers are genotyped—somewhere between half a million to 5 million markers—and each is looked at individually with respect to CLL, she said.
Unrelated cases and controls are included in the studies.
The first GWAS study identifying susceptibility loci for CLL was published in 2008. Subsequently, more studies were published with increasing sample sizes—more cases, more controls, and more genetic variants identified.
In the largest meta-analysis for CLL to date (Slager and Houlston et al, not yet published), investigators analyzed 4400 CLL cases and 13,000 controls.
They identified 9 more inherited variances with CLL, for a total of 43 identified to date.
The genes involved follow an apoptosis pathway, the telomere length pathway, and the B-cell lymphocyte development pathway.
“We have to remember, though, that these are non-causal,” Dr Slager cautioned. “We are just identifying the region in the genome that’s associated with CLL . . . . So now we have to dig deeper in these relationships to understand what’s going on.”
Using the identified CLL single-nucleotide polymorphisms, the investigators computed a polygenic risk score. CLL cases in the highest quintile had 2.7-fold increased risk of CLL.
However, the most common GWAS variants explain only 17% of the genetic heritability of CLL, which suggests that more loci are yet to be identified, Dr Slager clarified.
She went on to say that CLL incidence varies by ethnicity. Caucasians have a very high rate of CLL, while Asians have a very low rate. And African Americans have an incidence rate between those of Caucasians and Asians.
Investigators have hypothesized that the differences in incidence are based on the distinct genetic variants that are associated with the ethnicities.
For example, 4 of the variants with more than 20% frequency in Caucasians are quite rare in Chinese individuals and are also quite uncommon in African Americans, with frequencies less than 10%.
Dr Slager suggested that conducting these kinds of studies in Asians and African Americans will take a large sample size and most likely require an international consortium to bring enough CLL cases together.
Impact on clinical practice
Because of the strong genetic risk, patients with CLL naturally want to know about their offspring and their siblings, Dr Slager has found.
Patients who have monoclonal B-cell lymphocytosis (MBL), which is a precursor to CLL, pose the biggest quandary.
MBL is detected in about 5% of people over age 40. However, it’s detected in about 15% to 18% of people with a first-degree relative with CLL.
“These are individuals who have lymphocytosis,” Dr Slager said. “They come to your clinic and have an elevated blood cell count, flow cytometry. [So] you screen them for MBL, and these individuals who have more than 500 cells per microliter, they are the ones who progress to CLL, at 1% per year.”
Individuals who don’t have the elevated blood counts do have the clonal cells, Dr Slager noted.
“They just don’t have the expansion,” she said. “The progression of these individuals to CLL is still yet to be determined.”
For these reasons, Dr Slager believes “it’s still premature to bring genetic testing into clinical practice.”
Future directions include bringing together the non-environmental issues and the inherited issues to create a model that will accurately predict the risk of CLL.
Anticipate monoclonals in first-line therapy for multiple myeloma
NEW YORK – Monoclonal antibodies may soon have more of a role in the front-line treatment setting for multiple myeloma and as part of precollection/transplant regimens–or “so-called in vivo purges,” according to Tomer M. Mark, MD, of the department of clinical medicine at the Cornell University, New York.
They could also be used both in the preclinical setting for smoldering multiple myeloma, and for maintenance following transplant, which makes sense given that they are, for the most part, not myelosuppressive and have “very tolerable toxicities,” he said.
Myeloma is “sort of catching up to lymphoma in terms of antibody use and development. ... Approval trials are underway,” Dr. Mark said at Imedex: Lymphoma & Myeloma, an international congress on hematologic malignancies.
The successes of the phase III trials CASTOR and POLLUX in patients with relapsed and refractory multiple myeloma have paved the way for trials to examine daratumumab in first-line combination therapy.
In POLLUX, progression-free survival, time to progression, and overall response rate were superior with daratumumab in combination with lenalidomide/dexamethasone, as compared with lenalidomide/dexamethasone alone, in relapsed or refractory multiple myeloma patients. In CASTOR, daratumumab in combination with bortezomib and dexamethasone was superior to bortezomib and dexamethasone alone in a similar patient population. Of note, the effect was attenuated in those with multiple prior lines of treatment, which is, perhaps, an argument for moving monoclonal antibodies closer to the start of therapy, he said.
Daratumumab (Darzalex), which targets CD38, is currently indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent.
Similarly, elotuzumab (Empliciti), an immunostimulatory monoclonal antibody targeting a cell-surface receptor with both direct activation of natural killer cells and the capacity to trigger antibody-dependent, cell-mediated cytotoxicity of myeloma cells, is indicated in combination with lenalidomide/dexamethasone in patients who have received one to three therapies. Elotuzumab was shown in one trial to be associated with progression-free survival of 68% at 1 and 41% at 2 years when used with lenalidomide/dexamethasone. Patients receiving elotuzumab had a relative reduction of 30% in the risk of disease progression or death as compared with the control group.
In an ongoing trial with initial results reported at the 2015 American Society of Hematology annual meeting, elotuzumab with bortezomib/dexamethasone was associated with a more modest improvement in median progression-free survival, which was 9.9 months with triple therapy and 6.8 months with bortezomib/dexamethasone alone.
Both drugs have shown activity as single agents. In a phase I study, elotuzumab was associated with disease stability in 26% of patients, Dr. Mark said. Daratumumab, used as monotherapy in a study of relapsed or relapsed/refractory multiple myeloma patients, was associated with good overall response and progression-free survival, and “quite amazing” overall survival of 65%.
Other monoclonal antibodies in development include isatuximab (anti-CD38), lorvotuzumab mertansine (anti-CD56), and indatuximab ravtansine (anti-CD128), Dr. Mark said.
Dr. Mark reported receiving research funding from Celgene and Amgen, serving on speakers bureaus for Celgene, Millennium, Amgen, and Bristol-Myers Squibb, and serving on an advisory committee for Celgene and Millennium.
NEW YORK – Monoclonal antibodies may soon have more of a role in the front-line treatment setting for multiple myeloma and as part of precollection/transplant regimens–or “so-called in vivo purges,” according to Tomer M. Mark, MD, of the department of clinical medicine at the Cornell University, New York.
They could also be used both in the preclinical setting for smoldering multiple myeloma, and for maintenance following transplant, which makes sense given that they are, for the most part, not myelosuppressive and have “very tolerable toxicities,” he said.
Myeloma is “sort of catching up to lymphoma in terms of antibody use and development. ... Approval trials are underway,” Dr. Mark said at Imedex: Lymphoma & Myeloma, an international congress on hematologic malignancies.
The successes of the phase III trials CASTOR and POLLUX in patients with relapsed and refractory multiple myeloma have paved the way for trials to examine daratumumab in first-line combination therapy.
In POLLUX, progression-free survival, time to progression, and overall response rate were superior with daratumumab in combination with lenalidomide/dexamethasone, as compared with lenalidomide/dexamethasone alone, in relapsed or refractory multiple myeloma patients. In CASTOR, daratumumab in combination with bortezomib and dexamethasone was superior to bortezomib and dexamethasone alone in a similar patient population. Of note, the effect was attenuated in those with multiple prior lines of treatment, which is, perhaps, an argument for moving monoclonal antibodies closer to the start of therapy, he said.
Daratumumab (Darzalex), which targets CD38, is currently indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent.
Similarly, elotuzumab (Empliciti), an immunostimulatory monoclonal antibody targeting a cell-surface receptor with both direct activation of natural killer cells and the capacity to trigger antibody-dependent, cell-mediated cytotoxicity of myeloma cells, is indicated in combination with lenalidomide/dexamethasone in patients who have received one to three therapies. Elotuzumab was shown in one trial to be associated with progression-free survival of 68% at 1 and 41% at 2 years when used with lenalidomide/dexamethasone. Patients receiving elotuzumab had a relative reduction of 30% in the risk of disease progression or death as compared with the control group.
In an ongoing trial with initial results reported at the 2015 American Society of Hematology annual meeting, elotuzumab with bortezomib/dexamethasone was associated with a more modest improvement in median progression-free survival, which was 9.9 months with triple therapy and 6.8 months with bortezomib/dexamethasone alone.
Both drugs have shown activity as single agents. In a phase I study, elotuzumab was associated with disease stability in 26% of patients, Dr. Mark said. Daratumumab, used as monotherapy in a study of relapsed or relapsed/refractory multiple myeloma patients, was associated with good overall response and progression-free survival, and “quite amazing” overall survival of 65%.
Other monoclonal antibodies in development include isatuximab (anti-CD38), lorvotuzumab mertansine (anti-CD56), and indatuximab ravtansine (anti-CD128), Dr. Mark said.
Dr. Mark reported receiving research funding from Celgene and Amgen, serving on speakers bureaus for Celgene, Millennium, Amgen, and Bristol-Myers Squibb, and serving on an advisory committee for Celgene and Millennium.
NEW YORK – Monoclonal antibodies may soon have more of a role in the front-line treatment setting for multiple myeloma and as part of precollection/transplant regimens–or “so-called in vivo purges,” according to Tomer M. Mark, MD, of the department of clinical medicine at the Cornell University, New York.
They could also be used both in the preclinical setting for smoldering multiple myeloma, and for maintenance following transplant, which makes sense given that they are, for the most part, not myelosuppressive and have “very tolerable toxicities,” he said.
Myeloma is “sort of catching up to lymphoma in terms of antibody use and development. ... Approval trials are underway,” Dr. Mark said at Imedex: Lymphoma & Myeloma, an international congress on hematologic malignancies.
The successes of the phase III trials CASTOR and POLLUX in patients with relapsed and refractory multiple myeloma have paved the way for trials to examine daratumumab in first-line combination therapy.
In POLLUX, progression-free survival, time to progression, and overall response rate were superior with daratumumab in combination with lenalidomide/dexamethasone, as compared with lenalidomide/dexamethasone alone, in relapsed or refractory multiple myeloma patients. In CASTOR, daratumumab in combination with bortezomib and dexamethasone was superior to bortezomib and dexamethasone alone in a similar patient population. Of note, the effect was attenuated in those with multiple prior lines of treatment, which is, perhaps, an argument for moving monoclonal antibodies closer to the start of therapy, he said.
Daratumumab (Darzalex), which targets CD38, is currently indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent.
Similarly, elotuzumab (Empliciti), an immunostimulatory monoclonal antibody targeting a cell-surface receptor with both direct activation of natural killer cells and the capacity to trigger antibody-dependent, cell-mediated cytotoxicity of myeloma cells, is indicated in combination with lenalidomide/dexamethasone in patients who have received one to three therapies. Elotuzumab was shown in one trial to be associated with progression-free survival of 68% at 1 and 41% at 2 years when used with lenalidomide/dexamethasone. Patients receiving elotuzumab had a relative reduction of 30% in the risk of disease progression or death as compared with the control group.
In an ongoing trial with initial results reported at the 2015 American Society of Hematology annual meeting, elotuzumab with bortezomib/dexamethasone was associated with a more modest improvement in median progression-free survival, which was 9.9 months with triple therapy and 6.8 months with bortezomib/dexamethasone alone.
Both drugs have shown activity as single agents. In a phase I study, elotuzumab was associated with disease stability in 26% of patients, Dr. Mark said. Daratumumab, used as monotherapy in a study of relapsed or relapsed/refractory multiple myeloma patients, was associated with good overall response and progression-free survival, and “quite amazing” overall survival of 65%.
Other monoclonal antibodies in development include isatuximab (anti-CD38), lorvotuzumab mertansine (anti-CD56), and indatuximab ravtansine (anti-CD128), Dr. Mark said.
Dr. Mark reported receiving research funding from Celgene and Amgen, serving on speakers bureaus for Celgene, Millennium, Amgen, and Bristol-Myers Squibb, and serving on an advisory committee for Celgene and Millennium.
EXPERT ANALYSIS FROM IMEDEX: LYMPHOMA & MYELOMA
No longer a hand-me-down approach to WM
Photo courtesy of DFCI
NEW YORK—Whole-genome sequencing has changed the entire approach to drug development for Waldenström’s macroglobulinemia (WM), according to a speaker at Lymphoma & Myeloma 2016.
The strategy has changed from a hand-me-down one, relying on drugs developed first for other diseases, to a rational plan designed specifically to treat WM patients.
“We would wait for our colleagues in the myeloma world or lymphoma world, CLL world, anywhere we could find them, to help us with the development of drugs,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“And, sometimes, this resulted in delays of many, many years before those therapeutics could be vetted out and eventually be handed down to the Waldenström investigators.”
At Lymphoma & Myeloma 2016, Dr Treon described the current therapy of WM and the impact of the discovery of MYD88 and CXCR4 on drug development and treatment choices in WM.
Rituximab-based therapy
WM is a disease that strongly expresses CD20, even though it’s a lymphoplasmacytic disease. So rituximab, given alone and in combination, has been, to date, the most common approach to treating WM.
As a single agent, rituximab produces a response in 25% to 40% of WM patients, but these are very seldom deep responses, Dr Treon noted.
So investigators combined rituximab with cyclophosphamide, nucleoside analogues, proteasome inhibitors, and bendamustine, which increased the overall response rate and depth of response.
This translated into improvement in time to progression, which is now 4 to 5 years with these combination therapies.
“Now, the problem is, when you borrow things from other people, you sometimes end up with problems you didn’t anticipate,” Dr Treon said.
One of the unanticipated side effects with rituximab in WM patients is the IgM flare, which occurs in 40% to 60% of WM patients.
Rituximab can also cause hypogammaglobulinema, leading to infections, and results in a high intolerance rate, which tends to occur a few cycles into induction or maintenance therapy.
“In some cases,” Dr Treon advised, “a switch to ofatumumab, a fully human CD20 molecule, overcomes this intolerance.”
Nucleoside analogues, which used to be the mainstay of WM, have a high rate of transformation into a more aggressive lymphoma or acute myeloid leukemia.
Immunomodulatory drugs, particularly thalidomide, cause peripheral neuropathy greater than grade 2 in 60% of patients.
And a greater incidence of peripheral neuropathy is also observed with proteasome inhibitors, particularly bortezomib, in WM patients than in myeloma or mantle cell lymphoma patients.
“So this was at least the impetus for why we needed to develop novel approaches to treating this disease,” Dr Treon said.
MYD88 mutations
With whole-genome sequencing, investigators discovered that mutations in the MYD88 gene were highly prevalent in WM patients.
About 93% to 95% of WM patients have the L265P MYD88 mutation, and about 2% have the non-L265P MYD88 mutation.
MYD88 has prognostic significance in WM. Mutated MYD88 confers a better prognosis than unmutated MYD88.
MYD88 may also be important in predicting who will respond to drugs like ibrutinib.
CXCR4 mutations
Mutations in CXCR4 are the second most common mutation in WM.
Between 30% and 40% of WM patients have the WHIM-like CXCR4 C-tail mutations, which traffic the Waldenström’s cells to the bone marrow.
This mutation promotes drug resistance, including resistance to ibrutinib because of the enhanced AKT/ERK signaling.
Ibrutinib therapy
With this in mind, investigators set out to evaluate the potential of using a BTK inhibitor in relapsed/refractory WM patients and at the same time observe the genomics that might predict for response and resistance.
They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.
Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.
“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.”
The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort.
The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).
The progression-free survival at 2 years was 69% and overall survival was 95%.
At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia.
And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated.
Response to ibrutinib by mutation status
The overall response rate was 90% for all patients, but there were differences according to mutation status.
Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.
Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well.
If they also had a CXCR4WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%.
“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.
Patients with a CXCR4 mutation also respond more slowly than those without the mutation.
This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.
“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said.
“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.”
Ibrutinib in rituximab-refractory patients
A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.
The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.
Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.
Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.
The study was just accepted for publication in Lancet Oncology.
IRAK inhibition
Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.
So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.
Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.
“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”
Resistance to ibrutinib
Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds.
These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation.
C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.
So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.
Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase.
Other drugs being developed for WM include:
- Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
- Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
- Agents that block CXCR4 receptor signaling, such as ulocuplomab
- The BCL2 inhibitor venetoclax
- The CD38-targeted agent daratumumab.
Current treatment strategies
Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.
For patients with mutated MYD88 and no CXCR4 mutation:
- If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
- If patients have bulky disease, a combination of bendamustine and rituximab may be used.
- If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
- If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.
For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions.
To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib.
The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.
“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”
Bendamustine- or bortezomib-based therapy is effective in this population and can be considered.
In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.
Photo courtesy of DFCI
NEW YORK—Whole-genome sequencing has changed the entire approach to drug development for Waldenström’s macroglobulinemia (WM), according to a speaker at Lymphoma & Myeloma 2016.
The strategy has changed from a hand-me-down one, relying on drugs developed first for other diseases, to a rational plan designed specifically to treat WM patients.
“We would wait for our colleagues in the myeloma world or lymphoma world, CLL world, anywhere we could find them, to help us with the development of drugs,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“And, sometimes, this resulted in delays of many, many years before those therapeutics could be vetted out and eventually be handed down to the Waldenström investigators.”
At Lymphoma & Myeloma 2016, Dr Treon described the current therapy of WM and the impact of the discovery of MYD88 and CXCR4 on drug development and treatment choices in WM.
Rituximab-based therapy
WM is a disease that strongly expresses CD20, even though it’s a lymphoplasmacytic disease. So rituximab, given alone and in combination, has been, to date, the most common approach to treating WM.
As a single agent, rituximab produces a response in 25% to 40% of WM patients, but these are very seldom deep responses, Dr Treon noted.
So investigators combined rituximab with cyclophosphamide, nucleoside analogues, proteasome inhibitors, and bendamustine, which increased the overall response rate and depth of response.
This translated into improvement in time to progression, which is now 4 to 5 years with these combination therapies.
“Now, the problem is, when you borrow things from other people, you sometimes end up with problems you didn’t anticipate,” Dr Treon said.
One of the unanticipated side effects with rituximab in WM patients is the IgM flare, which occurs in 40% to 60% of WM patients.
Rituximab can also cause hypogammaglobulinema, leading to infections, and results in a high intolerance rate, which tends to occur a few cycles into induction or maintenance therapy.
“In some cases,” Dr Treon advised, “a switch to ofatumumab, a fully human CD20 molecule, overcomes this intolerance.”
Nucleoside analogues, which used to be the mainstay of WM, have a high rate of transformation into a more aggressive lymphoma or acute myeloid leukemia.
Immunomodulatory drugs, particularly thalidomide, cause peripheral neuropathy greater than grade 2 in 60% of patients.
And a greater incidence of peripheral neuropathy is also observed with proteasome inhibitors, particularly bortezomib, in WM patients than in myeloma or mantle cell lymphoma patients.
“So this was at least the impetus for why we needed to develop novel approaches to treating this disease,” Dr Treon said.
MYD88 mutations
With whole-genome sequencing, investigators discovered that mutations in the MYD88 gene were highly prevalent in WM patients.
About 93% to 95% of WM patients have the L265P MYD88 mutation, and about 2% have the non-L265P MYD88 mutation.
MYD88 has prognostic significance in WM. Mutated MYD88 confers a better prognosis than unmutated MYD88.
MYD88 may also be important in predicting who will respond to drugs like ibrutinib.
CXCR4 mutations
Mutations in CXCR4 are the second most common mutation in WM.
Between 30% and 40% of WM patients have the WHIM-like CXCR4 C-tail mutations, which traffic the Waldenström’s cells to the bone marrow.
This mutation promotes drug resistance, including resistance to ibrutinib because of the enhanced AKT/ERK signaling.
Ibrutinib therapy
With this in mind, investigators set out to evaluate the potential of using a BTK inhibitor in relapsed/refractory WM patients and at the same time observe the genomics that might predict for response and resistance.
They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.
Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.
“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.”
The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort.
The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).
The progression-free survival at 2 years was 69% and overall survival was 95%.
At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia.
And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated.
Response to ibrutinib by mutation status
The overall response rate was 90% for all patients, but there were differences according to mutation status.
Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.
Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well.
If they also had a CXCR4WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%.
“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.
Patients with a CXCR4 mutation also respond more slowly than those without the mutation.
This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.
“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said.
“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.”
Ibrutinib in rituximab-refractory patients
A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.
The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.
Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.
Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.
The study was just accepted for publication in Lancet Oncology.
IRAK inhibition
Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.
So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.
Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.
“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”
Resistance to ibrutinib
Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds.
These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation.
C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.
So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.
Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase.
Other drugs being developed for WM include:
- Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
- Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
- Agents that block CXCR4 receptor signaling, such as ulocuplomab
- The BCL2 inhibitor venetoclax
- The CD38-targeted agent daratumumab.
Current treatment strategies
Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.
For patients with mutated MYD88 and no CXCR4 mutation:
- If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
- If patients have bulky disease, a combination of bendamustine and rituximab may be used.
- If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
- If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.
For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions.
To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib.
The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.
“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”
Bendamustine- or bortezomib-based therapy is effective in this population and can be considered.
In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.
Photo courtesy of DFCI
NEW YORK—Whole-genome sequencing has changed the entire approach to drug development for Waldenström’s macroglobulinemia (WM), according to a speaker at Lymphoma & Myeloma 2016.
The strategy has changed from a hand-me-down one, relying on drugs developed first for other diseases, to a rational plan designed specifically to treat WM patients.
“We would wait for our colleagues in the myeloma world or lymphoma world, CLL world, anywhere we could find them, to help us with the development of drugs,” said Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“And, sometimes, this resulted in delays of many, many years before those therapeutics could be vetted out and eventually be handed down to the Waldenström investigators.”
At Lymphoma & Myeloma 2016, Dr Treon described the current therapy of WM and the impact of the discovery of MYD88 and CXCR4 on drug development and treatment choices in WM.
Rituximab-based therapy
WM is a disease that strongly expresses CD20, even though it’s a lymphoplasmacytic disease. So rituximab, given alone and in combination, has been, to date, the most common approach to treating WM.
As a single agent, rituximab produces a response in 25% to 40% of WM patients, but these are very seldom deep responses, Dr Treon noted.
So investigators combined rituximab with cyclophosphamide, nucleoside analogues, proteasome inhibitors, and bendamustine, which increased the overall response rate and depth of response.
This translated into improvement in time to progression, which is now 4 to 5 years with these combination therapies.
“Now, the problem is, when you borrow things from other people, you sometimes end up with problems you didn’t anticipate,” Dr Treon said.
One of the unanticipated side effects with rituximab in WM patients is the IgM flare, which occurs in 40% to 60% of WM patients.
Rituximab can also cause hypogammaglobulinema, leading to infections, and results in a high intolerance rate, which tends to occur a few cycles into induction or maintenance therapy.
“In some cases,” Dr Treon advised, “a switch to ofatumumab, a fully human CD20 molecule, overcomes this intolerance.”
Nucleoside analogues, which used to be the mainstay of WM, have a high rate of transformation into a more aggressive lymphoma or acute myeloid leukemia.
Immunomodulatory drugs, particularly thalidomide, cause peripheral neuropathy greater than grade 2 in 60% of patients.
And a greater incidence of peripheral neuropathy is also observed with proteasome inhibitors, particularly bortezomib, in WM patients than in myeloma or mantle cell lymphoma patients.
“So this was at least the impetus for why we needed to develop novel approaches to treating this disease,” Dr Treon said.
MYD88 mutations
With whole-genome sequencing, investigators discovered that mutations in the MYD88 gene were highly prevalent in WM patients.
About 93% to 95% of WM patients have the L265P MYD88 mutation, and about 2% have the non-L265P MYD88 mutation.
MYD88 has prognostic significance in WM. Mutated MYD88 confers a better prognosis than unmutated MYD88.
MYD88 may also be important in predicting who will respond to drugs like ibrutinib.
CXCR4 mutations
Mutations in CXCR4 are the second most common mutation in WM.
Between 30% and 40% of WM patients have the WHIM-like CXCR4 C-tail mutations, which traffic the Waldenström’s cells to the bone marrow.
This mutation promotes drug resistance, including resistance to ibrutinib because of the enhanced AKT/ERK signaling.
Ibrutinib therapy
With this in mind, investigators set out to evaluate the potential of using a BTK inhibitor in relapsed/refractory WM patients and at the same time observe the genomics that might predict for response and resistance.
They enrolled 63 patients in the multicenter study. Patients had a median of 2 prior therapies (range, 1–9), and 60% had bone marrow involvement.
Patients received single-agent ibrutinib at a dose of 420 mg orally each day until disease progression or the development of unacceptable toxic side effects.
“By the time they came back 4 weeks later to be evaluated, many of them were already in a response,” Dr Treon said. “And what we saw, in fact, was almost immediate improvement in hemoglobin, something that we didn’t see with many of our trials before that.”
The best IgM response reduced levels from 3520 to 880 mg/dL (P<0.001) for the entire cohort.
The best hemoglobin response increased hemoglobin levels 3 points, from 10.5 to 13.8 g/dL (P<0.001).
The progression-free survival at 2 years was 69% and overall survival was 95%.
At 37 months, most patients who achieve a response experience a durable, ongoing response, according to an update presented at the IX International Workshop on Waldenstrom’s Macroglobulinemia.
And toxicities were “very much in line with what our colleagues have seen in other disease groups,” Dr Treon stated.
Response to ibrutinib by mutation status
The overall response rate was 90% for all patients, but there were differences according to mutation status.
Patients with no MYD88 mutation and no CXCR4 mutation had absolutely no major response.
Patients with a MYD88 mutation responded at an overall rate of 100% and had a major response rate of 91.7% if they did not have a CXCR4 mutation as well.
If they also had a CXCR4WHIM mutation, the overall response rate was lower, at 85.7%, and the major response rate was 61.9%.
“It’s still something to be incredibly excited about—61.9% single-agent activity,” Dr Treon said.
Patients with a CXCR4 mutation also respond more slowly than those without the mutation.
This investigator-sponsored study led to the approval of ibrutinib in WM in the US as well as in Europe and Canada.
“And the point to make about this is that investigators can bring their data to the FDA, the EMA, even Canada, and it can make a difference,” Dr Treon said.
“We don’t always have to have company-sponsored registration studies to be able to make these kinds of advances.”
Ibrutinib in rituximab-refractory patients
A multicenter, phase 3 study of ibrutinib in rituximab-refractory patients was “almost a photocopy of our study,” Dr Treon said.
The main difference was that the patients were even sicker, having failed a median of 4 prior therapies.
Patients experienced rapid improvements in hemoglobin and IgM levels and had an overall response rate of 90%.
Patients with a CXCR4 mutation also tended to lag in terms of pace of hemoglobin improvement and reduction in IgM.
The study was just accepted for publication in Lancet Oncology.
IRAK inhibition
Investigators were puzzled by the paucity of complete responses with ibrutinib, and they found the IRAK pathway remained turned on in patients treated with ibrutinib.
So they took cells of patients treated for 6 months with ibrutinib and co-cultured them with ibrutinib and an IRAK inhibitor. They observed the induction of apoptosis.
Based on this finding, the investigators are manufacturing a very potent IRAK1 inhibitor (JH-X-119), which, when combined with ibrutinib, synergistically increases tumor-cell killing.
“And so one of the strategies we have going forward,” Dr Treon said, “is the ability to advance ibrutinib therapy in MYD88-mutated tumors by the addition of the IRAK inhibitor.”
Resistance to ibrutinib
Investigators have found multiple mutations in the C481 site in individual WM patients, which is where ibrutinib binds.
These mutations represent a minority of the clone, but they exert almost a fully clonal signature. The few patients with these mutations also have a CXCR4 mutation.
C481 mutations shift the signaling of cells in the presence of ibrutinib toward ERK, which is a very powerful survival pathway.
So investigators are examining whether an ERK inhibitor combined with ibrutinib can elicit synergistic killing of BTK-resistant cells.
Investigators have also been synthesizing potent HCK inhibitors, which might overcome BTK mutations by shutting down the ability to activate Bruton’s tyrosine kinase.
Other drugs being developed for WM include:
- Combinations with a proteasome inhibitor, such as ixazomib, dexamethasone, and rituximab
- Agents that target MYD88 signaling, such as the BTK inhibitors acalabrutinib and BGB-3111
- Agents that block CXCR4 receptor signaling, such as ulocuplomab
- The BCL2 inhibitor venetoclax
- The CD38-targeted agent daratumumab.
Current treatment strategies
Knowing a patient’s MYD88 and CXCR4 mutation status provides an opportunity to take a rational approach to treating individuals with WM, Dr Treon said.
For patients with mutated MYD88 and no CXCR4 mutation:
- If patients do not have bulky disease or contraindications, ibrutinib may be used if available.
- If patients have bulky disease, a combination of bendamustine and rituximab may be used.
- If patients have amyloidosis, a combination of bortezomib, dexamethasone, and rituximab is possible.
- If patients have IgM peripheral neuropathy, then rituximab with or without an alkylator is recommended.
For patients with mutated MYD88 and mutated CXCR4, the same treatments can be used as for patients with mutated MYD88 and unmutated CXCR4 with the same restrictions.
To achieve an immediate response for patients with a CXCR4 mutation, an alternative therapy to ibrutinib—such as the bendamustine, dexamethasone, rituximab combination—may be the best choice, because CXCR4-mutated individuals have a slower response to ibrutinib.
The problem arises with the MYD88-wild-type patients, because their survival is poorer than the MYD88-mutated patients.
“We still don’t know what’s wrong with these individuals,” Dr Treon said. “We don’t have any idea about what their basic genomic problems are.”
Bendamustine- or bortezomib-based therapy is effective in this population and can be considered.
In terms of salvage therapy, “the only thing to keep in mind is that if something worked the first time and you got at least a 2-year response with it, you can go back and consider it,” Dr Treon said.
Speaker says use the best regimen ASAP in MM
NEW YORK—It’s important to use the best possible regimen as soon as possible when treating patients with multiple myeloma (MM), according to a speaker at Lymphoma & Myeloma 2016.
Antonio Palumbo, MD, of the University of Torino in Italy, explained that the urgency, from a biological point of view, is because myeloma accumulates genetic mutations that change the disease in a “dramatic way.”
“At diagnosis, you might have 5000 mutations, and, at first relapse, there are 12,000 mutations,” he said. “They are completely different tumors. So the first thing that we have to recognize is that, with time, myeloma is not the same. It’s becoming different tumors.”
Dr Palumbo noted that early intervention is important because genetic and epigenetic abnormalities increase as the disease progresses and becomes more resistant.
For example, if 100 patients receive first-line treatment, 40 of them will not reach the second line. Only 60 patients will receive second-line therapy, and only 35 patients will receive third-line treatment. By the fifth line, only 10 patients, or 10%, will receive it.
“If you have very good genomic stability, you can become sensitive to different treatments,” Dr Palumbo said. “But if you become a different disease, you will not be able to receive the next therapy. That’s why it’s so important . . . to use the best possible regimen as soon as possible.”
Best regimens
The triplet bortezomib-lenalidomide-dexamethasone is the “best possible regimen today,” Dr Palumbo said, “followed by continuous therapy.”
The 2-drug combination of lenalidomide and dexamethasone is probably more suitable for the elderly and the frail.
Alternative regimens include carfilzomib-cyclophosphamide-dexamethasone and ixazomib-lenalidomide-dexamethasone.
Continuous therapy
Continuous therapy has been “one of the major achievements” in the treatment of MM, Dr Palumbo said. Without continuous therapy, patients in complete response remain so for about 1 year when treated with conventional chemotherapy.
Investigators found that maintenance therapy significantly prolongs progression-free survival and overall survival (P=0.02). They recommend intensification with maintenance to optimize treatment efficacy and prolong survival.
Immunomodulatory drugs such as lenalidomide are the backbone of continuous therapy today.
However, ixazomib represents another option. Ixazomib maintenance has been shown to produce durable responses for a median of more than 2 years in previously untreated patients not undergoing autologous stem cell transplant.
Salvage therapy
Seven combinations are now available for salvage therapy, including those with proteasome inhibitors, monoclonal antibodies, pomalidomide, and histone deacetylase inhibitors.
Included in some of these combinations are the newer agents ixazomib, elotuzumab, and daratumumab, “which many might consider the new rituximab,” Dr Palumbo said.
Risk stratification
Dr Palumbo stressed the importance of risk stratification—both in clinical trials and in practice.
“[T]he moment you under-treat a patient, you transform a good-risk patient into a high-risk patient . . . ,” he said.
And if trials comparing treatments are not conducted within risk categories, researchers are comparing apples to oranges—good risk with high risk
The Revised International Staging System (R-ISS) for MM effectively stratifies newly diagnosed patients by combining the original ISS, chromosomal abnormalities, and serum lactate dehydrogenase levels to evaluate prognosis.
The R-ISS defines 3 new, distinct categories that researchers believe effectively define patients’ relative risk with respect to their survival.
Age and frailty
MM patients generally fall into 3 age categories: 25-64, 65-74, and 75-101.
The youngest group can receive autologous transplant, the fit patients ages 65 to 74 can receive full-dose chemotherapy, and the oldest, frailer patients should receive reduced-dose chemotherapy.
“It’s important to differentiate fit from frail,” Dr Palumbo said, “because we cannot give the same treatment schema to a 55-year-old versus 65 or 85. At 85, that schema would create a lot of toxicities.”
In frail patients, it’s always important to check which comorbidities are present using the Charlson comorbidity scale, Dr Palumbo said.
“Remember, when we put together age, chromosome abnormalities, and frailty, frailty is the most relevant prognostic factor when you add everything together,” he said.
“Two drugs versus 3 drugs doesn’t make much difference when you are starting to introduce treatment to these very frail patients with comorbidities.”
Minimal residual disease
Dr Palumbo indicated that a combination of MRI and PET-CT should be used for a more accurate indication of minimal residual disease.
“[W]e hope to have cure, [but] I don’t think, today, myeloma is a curable disease,” he said.
He clarified this by saying that patients who are in complete response and minimal residual disease-negative at 3 years do well, but, by 7 years, “something is happening.”
And at 10 years, progression-free survival has dropped off significantly, “telling us that cure is probably not yet there.”
NEW YORK—It’s important to use the best possible regimen as soon as possible when treating patients with multiple myeloma (MM), according to a speaker at Lymphoma & Myeloma 2016.
Antonio Palumbo, MD, of the University of Torino in Italy, explained that the urgency, from a biological point of view, is because myeloma accumulates genetic mutations that change the disease in a “dramatic way.”
“At diagnosis, you might have 5000 mutations, and, at first relapse, there are 12,000 mutations,” he said. “They are completely different tumors. So the first thing that we have to recognize is that, with time, myeloma is not the same. It’s becoming different tumors.”
Dr Palumbo noted that early intervention is important because genetic and epigenetic abnormalities increase as the disease progresses and becomes more resistant.
For example, if 100 patients receive first-line treatment, 40 of them will not reach the second line. Only 60 patients will receive second-line therapy, and only 35 patients will receive third-line treatment. By the fifth line, only 10 patients, or 10%, will receive it.
“If you have very good genomic stability, you can become sensitive to different treatments,” Dr Palumbo said. “But if you become a different disease, you will not be able to receive the next therapy. That’s why it’s so important . . . to use the best possible regimen as soon as possible.”
Best regimens
The triplet bortezomib-lenalidomide-dexamethasone is the “best possible regimen today,” Dr Palumbo said, “followed by continuous therapy.”
The 2-drug combination of lenalidomide and dexamethasone is probably more suitable for the elderly and the frail.
Alternative regimens include carfilzomib-cyclophosphamide-dexamethasone and ixazomib-lenalidomide-dexamethasone.
Continuous therapy
Continuous therapy has been “one of the major achievements” in the treatment of MM, Dr Palumbo said. Without continuous therapy, patients in complete response remain so for about 1 year when treated with conventional chemotherapy.
Investigators found that maintenance therapy significantly prolongs progression-free survival and overall survival (P=0.02). They recommend intensification with maintenance to optimize treatment efficacy and prolong survival.
Immunomodulatory drugs such as lenalidomide are the backbone of continuous therapy today.
However, ixazomib represents another option. Ixazomib maintenance has been shown to produce durable responses for a median of more than 2 years in previously untreated patients not undergoing autologous stem cell transplant.
Salvage therapy
Seven combinations are now available for salvage therapy, including those with proteasome inhibitors, monoclonal antibodies, pomalidomide, and histone deacetylase inhibitors.
Included in some of these combinations are the newer agents ixazomib, elotuzumab, and daratumumab, “which many might consider the new rituximab,” Dr Palumbo said.
Risk stratification
Dr Palumbo stressed the importance of risk stratification—both in clinical trials and in practice.
“[T]he moment you under-treat a patient, you transform a good-risk patient into a high-risk patient . . . ,” he said.
And if trials comparing treatments are not conducted within risk categories, researchers are comparing apples to oranges—good risk with high risk
The Revised International Staging System (R-ISS) for MM effectively stratifies newly diagnosed patients by combining the original ISS, chromosomal abnormalities, and serum lactate dehydrogenase levels to evaluate prognosis.
The R-ISS defines 3 new, distinct categories that researchers believe effectively define patients’ relative risk with respect to their survival.
Age and frailty
MM patients generally fall into 3 age categories: 25-64, 65-74, and 75-101.
The youngest group can receive autologous transplant, the fit patients ages 65 to 74 can receive full-dose chemotherapy, and the oldest, frailer patients should receive reduced-dose chemotherapy.
“It’s important to differentiate fit from frail,” Dr Palumbo said, “because we cannot give the same treatment schema to a 55-year-old versus 65 or 85. At 85, that schema would create a lot of toxicities.”
In frail patients, it’s always important to check which comorbidities are present using the Charlson comorbidity scale, Dr Palumbo said.
“Remember, when we put together age, chromosome abnormalities, and frailty, frailty is the most relevant prognostic factor when you add everything together,” he said.
“Two drugs versus 3 drugs doesn’t make much difference when you are starting to introduce treatment to these very frail patients with comorbidities.”
Minimal residual disease
Dr Palumbo indicated that a combination of MRI and PET-CT should be used for a more accurate indication of minimal residual disease.
“[W]e hope to have cure, [but] I don’t think, today, myeloma is a curable disease,” he said.
He clarified this by saying that patients who are in complete response and minimal residual disease-negative at 3 years do well, but, by 7 years, “something is happening.”
And at 10 years, progression-free survival has dropped off significantly, “telling us that cure is probably not yet there.”
NEW YORK—It’s important to use the best possible regimen as soon as possible when treating patients with multiple myeloma (MM), according to a speaker at Lymphoma & Myeloma 2016.
Antonio Palumbo, MD, of the University of Torino in Italy, explained that the urgency, from a biological point of view, is because myeloma accumulates genetic mutations that change the disease in a “dramatic way.”
“At diagnosis, you might have 5000 mutations, and, at first relapse, there are 12,000 mutations,” he said. “They are completely different tumors. So the first thing that we have to recognize is that, with time, myeloma is not the same. It’s becoming different tumors.”
Dr Palumbo noted that early intervention is important because genetic and epigenetic abnormalities increase as the disease progresses and becomes more resistant.
For example, if 100 patients receive first-line treatment, 40 of them will not reach the second line. Only 60 patients will receive second-line therapy, and only 35 patients will receive third-line treatment. By the fifth line, only 10 patients, or 10%, will receive it.
“If you have very good genomic stability, you can become sensitive to different treatments,” Dr Palumbo said. “But if you become a different disease, you will not be able to receive the next therapy. That’s why it’s so important . . . to use the best possible regimen as soon as possible.”
Best regimens
The triplet bortezomib-lenalidomide-dexamethasone is the “best possible regimen today,” Dr Palumbo said, “followed by continuous therapy.”
The 2-drug combination of lenalidomide and dexamethasone is probably more suitable for the elderly and the frail.
Alternative regimens include carfilzomib-cyclophosphamide-dexamethasone and ixazomib-lenalidomide-dexamethasone.
Continuous therapy
Continuous therapy has been “one of the major achievements” in the treatment of MM, Dr Palumbo said. Without continuous therapy, patients in complete response remain so for about 1 year when treated with conventional chemotherapy.
Investigators found that maintenance therapy significantly prolongs progression-free survival and overall survival (P=0.02). They recommend intensification with maintenance to optimize treatment efficacy and prolong survival.
Immunomodulatory drugs such as lenalidomide are the backbone of continuous therapy today.
However, ixazomib represents another option. Ixazomib maintenance has been shown to produce durable responses for a median of more than 2 years in previously untreated patients not undergoing autologous stem cell transplant.
Salvage therapy
Seven combinations are now available for salvage therapy, including those with proteasome inhibitors, monoclonal antibodies, pomalidomide, and histone deacetylase inhibitors.
Included in some of these combinations are the newer agents ixazomib, elotuzumab, and daratumumab, “which many might consider the new rituximab,” Dr Palumbo said.
Risk stratification
Dr Palumbo stressed the importance of risk stratification—both in clinical trials and in practice.
“[T]he moment you under-treat a patient, you transform a good-risk patient into a high-risk patient . . . ,” he said.
And if trials comparing treatments are not conducted within risk categories, researchers are comparing apples to oranges—good risk with high risk
The Revised International Staging System (R-ISS) for MM effectively stratifies newly diagnosed patients by combining the original ISS, chromosomal abnormalities, and serum lactate dehydrogenase levels to evaluate prognosis.
The R-ISS defines 3 new, distinct categories that researchers believe effectively define patients’ relative risk with respect to their survival.
Age and frailty
MM patients generally fall into 3 age categories: 25-64, 65-74, and 75-101.
The youngest group can receive autologous transplant, the fit patients ages 65 to 74 can receive full-dose chemotherapy, and the oldest, frailer patients should receive reduced-dose chemotherapy.
“It’s important to differentiate fit from frail,” Dr Palumbo said, “because we cannot give the same treatment schema to a 55-year-old versus 65 or 85. At 85, that schema would create a lot of toxicities.”
In frail patients, it’s always important to check which comorbidities are present using the Charlson comorbidity scale, Dr Palumbo said.
“Remember, when we put together age, chromosome abnormalities, and frailty, frailty is the most relevant prognostic factor when you add everything together,” he said.
“Two drugs versus 3 drugs doesn’t make much difference when you are starting to introduce treatment to these very frail patients with comorbidities.”
Minimal residual disease
Dr Palumbo indicated that a combination of MRI and PET-CT should be used for a more accurate indication of minimal residual disease.
“[W]e hope to have cure, [but] I don’t think, today, myeloma is a curable disease,” he said.
He clarified this by saying that patients who are in complete response and minimal residual disease-negative at 3 years do well, but, by 7 years, “something is happening.”
And at 10 years, progression-free survival has dropped off significantly, “telling us that cure is probably not yet there.”