Prognostic factors guide mantle cell treatment decisions

 

CHICAGO – The treatment options for patients with mantle cell lymphoma (MCL) vary based on age, but several prognostic factors can help guide treatment decision making in all patients, according to Kristie A. Blum, MD.

These include age, disease stage, disease sites, Mantle Cell Lymphoma International Prognostic Index (MIPI), biologic factors, and histology, Dr. Blum said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

Age

“I think the most important thing to recognize is there really isn’t any randomized transplant data for patients that are over 65. … There are very few transplant studies for patients [aged] 66-70,” said Dr. Blum, acting professor of hematology and medical oncology at Emory University in Atlanta.

The SWOG 0213 study did examine rituximab-hyperCVAD (R-HCVAD) in this age group, and showed that it has higher toxicity and lower efficacy in older versus younger patients, she said.

“Of course this is not typically a transplant approach, but an intensive-therapy approach,” she said, noting that progression-free and overall survival in patients aged 66-70 years were just 29% and 57%, respectively (Ann Oncol. 2013 Jun; 24[6]:1587-93).

The CALGB 59909 and 50403 studies of chemoimmunotherapy and autologous stem cell transplant (ASCT), with or without bortezomib, included only adults up to age 70.

“So while most of us think that transplant is probably okay and safe in patients up to 70, the question is what induction regimen to use,” she said.

Dr. Blum noted that a retrospective study from the Mayo Clinic looked at all 63 patients aged 65 years and older with MCL who underwent ASCT there (including 22 patients over age 70), and most (60%) were treated with R-CHOP. Just 19% received cytarabine-based regimens (Blood. 2017:130:4536).

Median overall survival after ASCT was 5 years, and median relapse-free survival was 3.2 years.

 

Stage

Like age, disease stage in MCL patients has not been well studied, Dr. Blum said.

“Most of the randomized transplant studies have been conducted in patients stage II-IV, so we don’t have a lot of data about the early-stage patients,” she said, adding, however, that there are some retrospective data on radiation therapy for stage I-II MCL in older adults.

An International Lymphoma Radiation Oncology Group study of 179 patients, for example, showed that overall survival was “really the same whether they got chemo, chemo plus radiation, or radiation alone,” she said.

The 10-year freedom from progression was 46%, 43%, and 31%, respectively (P = .64).
 

Location

“What about where the disease presents? We’ve all heard about indolent mantle cell – so there’s this leukemic ‘non-nodal’ variant that’s been described,” she said, noting that this variant has a chronic lymphocytic leukemia–like presentation (no nodal disease, blood and marrow involvement, and splenic involvement). “And they tend to be SOX11-negative with mutated [immunoglobulin variable region heavy chain gene].”

Another variant involves primarily nodal disease that typically presents without elevated white blood cell count, with low Ki-67 (10% or lower), with SOX11 positivity, and without TP53 mutations.

“But I would caution you that this is really not very well defined; there’s no clear marker that predicts for indolent disease,” Dr. Blum said. “If you have one of these patients and you’re thinking about observing them, my experience has been that the most important thing to do is make sure you look at their [gastrointestinal] tract. I’ve had a lot of these patients progress with colon masses over time.”
 

 

MIPI

MIPI is basically a risk score calculated based on age, performance status, lactate dehydrogenase levels, and white cell count, she said.

MIPI less than 5.70 indicates low risk, MIPI of 5.70-6.2 is considered intermediate risk, and MIPI greater than 6.2 is considered high risk. High-risk patients who were transplanted in one study had a median overall survival of about 2.8 years and a median time to treatment failure of 1.4 years (J Clin Oncol. 2014 May 1;32[13]:1338-46). Even among patients under age 65 with high risk, the median time to treatment failure was 2 years, she said.

“So I do wonder, are we really helping these patients by transplanting them?” she added. “Similarly, the low-risk patients had a median time to treatment failure of 6 years; I wonder if they didn’t need a transplant.”

Biology

Ki-67 protein, a cellular marker for proliferation, is another important prognostic factor. A European Mantle Cell network study showed that median overall survival for patients with a Ki-67 proliferation index of less than 30% was not reached, and 5-year survival was 75%. At the same time, the median overall survival (OS) for those with Ki-67 proliferation index of 30% or greater was just 3.4 years, and 5-year OS was only 41% (J Clin Oncol. 2016 Apr 20;34[12]:1386-94).

The prognostic effect was independent of induction treatment, Dr. Blum said.

Combining MIPI and the Ki-67 index (MIPI-C) provides further value in defining a very high-risk group; those with both high MIPI and high Ki-67 had a median overall survival of only 1.5 years, and those with both, but who were under age 65, had median OS of only 1.7 years.
 

Histology

Patients with blastoid MCL variants were shown in that same study to have median OS of about 2.8 years, compared with 8 years in those with nonblastoid variants. The 5-year OS and progression-free survival (PFS) for blastoid variants were 35% and 29%, respectively, and for nonblastoid variants were 68% and 44%, respectively.

“But when you look at this with respect to the Ki-67 – so those patients that were called nonblastoid, that had a high Ki-67 index – their median overall survival is still lower at 5 years,” she said, noting that median OS was not reached in blastic variant (low-Ki-67) patients. “So it seems like the prognostic effect of cytology is largely explained by the Ki-67 index.”

In terms of karyotype, several studies have shown that complex karyotype is associated with poorer outcomes. One recent multicenter study of 274 patients showed that median OS in 53 patients with at least three cytogenetic abnormalities versus the remaining patients was 4.5 years vs. 11.6 years, and median PFS was 1.9 vs. 4.4 years (Cancer. 2018 Jun 1;124[11]:2306-15).

TP53 deletions (which affect about 20% of MCL patients) and mutations (which affect about 10%), are also useful prognostic factors, she said, noting that each is associated with inferior outcomes, and in one study patients with both appeared to have the worst outcomes (Blood. 2017;130:1903-10).

Another study showed that high TP53 staining (greater than 50% positive) is also associated with inferior outcomes, including reduced time to treatment failure and lower overall survival (Blood. 2018;131:417-20).

Finally, the most important factor is the patient’s wishes, Dr. Blum said, noting that she has “a lot of long discussions with these patients.”

“I consider all of these factors with each patient that I see with mantle cell,” she said.

Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.

[email protected]

 

CHICAGO – The treatment options for patients with mantle cell lymphoma (MCL) vary based on age, but several prognostic factors can help guide treatment decision making in all patients, according to Kristie A. Blum, MD.

These include age, disease stage, disease sites, Mantle Cell Lymphoma International Prognostic Index (MIPI), biologic factors, and histology, Dr. Blum said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

Age

“I think the most important thing to recognize is there really isn’t any randomized transplant data for patients that are over 65. … There are very few transplant studies for patients [aged] 66-70,” said Dr. Blum, acting professor of hematology and medical oncology at Emory University in Atlanta.

The SWOG 0213 study did examine rituximab-hyperCVAD (R-HCVAD) in this age group, and showed that it has higher toxicity and lower efficacy in older versus younger patients, she said.

“Of course this is not typically a transplant approach, but an intensive-therapy approach,” she said, noting that progression-free and overall survival in patients aged 66-70 years were just 29% and 57%, respectively (Ann Oncol. 2013 Jun; 24[6]:1587-93).

The CALGB 59909 and 50403 studies of chemoimmunotherapy and autologous stem cell transplant (ASCT), with or without bortezomib, included only adults up to age 70.

“So while most of us think that transplant is probably okay and safe in patients up to 70, the question is what induction regimen to use,” she said.

Dr. Blum noted that a retrospective study from the Mayo Clinic looked at all 63 patients aged 65 years and older with MCL who underwent ASCT there (including 22 patients over age 70), and most (60%) were treated with R-CHOP. Just 19% received cytarabine-based regimens (Blood. 2017:130:4536).

Median overall survival after ASCT was 5 years, and median relapse-free survival was 3.2 years.

 

Stage

Like age, disease stage in MCL patients has not been well studied, Dr. Blum said.

“Most of the randomized transplant studies have been conducted in patients stage II-IV, so we don’t have a lot of data about the early-stage patients,” she said, adding, however, that there are some retrospective data on radiation therapy for stage I-II MCL in older adults.

An International Lymphoma Radiation Oncology Group study of 179 patients, for example, showed that overall survival was “really the same whether they got chemo, chemo plus radiation, or radiation alone,” she said.

The 10-year freedom from progression was 46%, 43%, and 31%, respectively (P = .64).
 

Location

“What about where the disease presents? We’ve all heard about indolent mantle cell – so there’s this leukemic ‘non-nodal’ variant that’s been described,” she said, noting that this variant has a chronic lymphocytic leukemia–like presentation (no nodal disease, blood and marrow involvement, and splenic involvement). “And they tend to be SOX11-negative with mutated [immunoglobulin variable region heavy chain gene].”

Another variant involves primarily nodal disease that typically presents without elevated white blood cell count, with low Ki-67 (10% or lower), with SOX11 positivity, and without TP53 mutations.

“But I would caution you that this is really not very well defined; there’s no clear marker that predicts for indolent disease,” Dr. Blum said. “If you have one of these patients and you’re thinking about observing them, my experience has been that the most important thing to do is make sure you look at their [gastrointestinal] tract. I’ve had a lot of these patients progress with colon masses over time.”
 

 

MIPI

MIPI is basically a risk score calculated based on age, performance status, lactate dehydrogenase levels, and white cell count, she said.

MIPI less than 5.70 indicates low risk, MIPI of 5.70-6.2 is considered intermediate risk, and MIPI greater than 6.2 is considered high risk. High-risk patients who were transplanted in one study had a median overall survival of about 2.8 years and a median time to treatment failure of 1.4 years (J Clin Oncol. 2014 May 1;32[13]:1338-46). Even among patients under age 65 with high risk, the median time to treatment failure was 2 years, she said.

“So I do wonder, are we really helping these patients by transplanting them?” she added. “Similarly, the low-risk patients had a median time to treatment failure of 6 years; I wonder if they didn’t need a transplant.”

Biology

Ki-67 protein, a cellular marker for proliferation, is another important prognostic factor. A European Mantle Cell network study showed that median overall survival for patients with a Ki-67 proliferation index of less than 30% was not reached, and 5-year survival was 75%. At the same time, the median overall survival (OS) for those with Ki-67 proliferation index of 30% or greater was just 3.4 years, and 5-year OS was only 41% (J Clin Oncol. 2016 Apr 20;34[12]:1386-94).

The prognostic effect was independent of induction treatment, Dr. Blum said.

Combining MIPI and the Ki-67 index (MIPI-C) provides further value in defining a very high-risk group; those with both high MIPI and high Ki-67 had a median overall survival of only 1.5 years, and those with both, but who were under age 65, had median OS of only 1.7 years.
 

Histology

Patients with blastoid MCL variants were shown in that same study to have median OS of about 2.8 years, compared with 8 years in those with nonblastoid variants. The 5-year OS and progression-free survival (PFS) for blastoid variants were 35% and 29%, respectively, and for nonblastoid variants were 68% and 44%, respectively.

“But when you look at this with respect to the Ki-67 – so those patients that were called nonblastoid, that had a high Ki-67 index – their median overall survival is still lower at 5 years,” she said, noting that median OS was not reached in blastic variant (low-Ki-67) patients. “So it seems like the prognostic effect of cytology is largely explained by the Ki-67 index.”

In terms of karyotype, several studies have shown that complex karyotype is associated with poorer outcomes. One recent multicenter study of 274 patients showed that median OS in 53 patients with at least three cytogenetic abnormalities versus the remaining patients was 4.5 years vs. 11.6 years, and median PFS was 1.9 vs. 4.4 years (Cancer. 2018 Jun 1;124[11]:2306-15).

TP53 deletions (which affect about 20% of MCL patients) and mutations (which affect about 10%), are also useful prognostic factors, she said, noting that each is associated with inferior outcomes, and in one study patients with both appeared to have the worst outcomes (Blood. 2017;130:1903-10).

Another study showed that high TP53 staining (greater than 50% positive) is also associated with inferior outcomes, including reduced time to treatment failure and lower overall survival (Blood. 2018;131:417-20).

Finally, the most important factor is the patient’s wishes, Dr. Blum said, noting that she has “a lot of long discussions with these patients.”

“I consider all of these factors with each patient that I see with mantle cell,” she said.

Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.

[email protected]

 

CHICAGO – The treatment options for patients with mantle cell lymphoma (MCL) vary based on age, but several prognostic factors can help guide treatment decision making in all patients, according to Kristie A. Blum, MD.

These include age, disease stage, disease sites, Mantle Cell Lymphoma International Prognostic Index (MIPI), biologic factors, and histology, Dr. Blum said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

Age

“I think the most important thing to recognize is there really isn’t any randomized transplant data for patients that are over 65. … There are very few transplant studies for patients [aged] 66-70,” said Dr. Blum, acting professor of hematology and medical oncology at Emory University in Atlanta.

The SWOG 0213 study did examine rituximab-hyperCVAD (R-HCVAD) in this age group, and showed that it has higher toxicity and lower efficacy in older versus younger patients, she said.

“Of course this is not typically a transplant approach, but an intensive-therapy approach,” she said, noting that progression-free and overall survival in patients aged 66-70 years were just 29% and 57%, respectively (Ann Oncol. 2013 Jun; 24[6]:1587-93).

The CALGB 59909 and 50403 studies of chemoimmunotherapy and autologous stem cell transplant (ASCT), with or without bortezomib, included only adults up to age 70.

“So while most of us think that transplant is probably okay and safe in patients up to 70, the question is what induction regimen to use,” she said.

Dr. Blum noted that a retrospective study from the Mayo Clinic looked at all 63 patients aged 65 years and older with MCL who underwent ASCT there (including 22 patients over age 70), and most (60%) were treated with R-CHOP. Just 19% received cytarabine-based regimens (Blood. 2017:130:4536).

Median overall survival after ASCT was 5 years, and median relapse-free survival was 3.2 years.

 

Stage

Like age, disease stage in MCL patients has not been well studied, Dr. Blum said.

“Most of the randomized transplant studies have been conducted in patients stage II-IV, so we don’t have a lot of data about the early-stage patients,” she said, adding, however, that there are some retrospective data on radiation therapy for stage I-II MCL in older adults.

An International Lymphoma Radiation Oncology Group study of 179 patients, for example, showed that overall survival was “really the same whether they got chemo, chemo plus radiation, or radiation alone,” she said.

The 10-year freedom from progression was 46%, 43%, and 31%, respectively (P = .64).
 

Location

“What about where the disease presents? We’ve all heard about indolent mantle cell – so there’s this leukemic ‘non-nodal’ variant that’s been described,” she said, noting that this variant has a chronic lymphocytic leukemia–like presentation (no nodal disease, blood and marrow involvement, and splenic involvement). “And they tend to be SOX11-negative with mutated [immunoglobulin variable region heavy chain gene].”

Another variant involves primarily nodal disease that typically presents without elevated white blood cell count, with low Ki-67 (10% or lower), with SOX11 positivity, and without TP53 mutations.

“But I would caution you that this is really not very well defined; there’s no clear marker that predicts for indolent disease,” Dr. Blum said. “If you have one of these patients and you’re thinking about observing them, my experience has been that the most important thing to do is make sure you look at their [gastrointestinal] tract. I’ve had a lot of these patients progress with colon masses over time.”
 

 

MIPI

MIPI is basically a risk score calculated based on age, performance status, lactate dehydrogenase levels, and white cell count, she said.

MIPI less than 5.70 indicates low risk, MIPI of 5.70-6.2 is considered intermediate risk, and MIPI greater than 6.2 is considered high risk. High-risk patients who were transplanted in one study had a median overall survival of about 2.8 years and a median time to treatment failure of 1.4 years (J Clin Oncol. 2014 May 1;32[13]:1338-46). Even among patients under age 65 with high risk, the median time to treatment failure was 2 years, she said.

“So I do wonder, are we really helping these patients by transplanting them?” she added. “Similarly, the low-risk patients had a median time to treatment failure of 6 years; I wonder if they didn’t need a transplant.”

Biology

Ki-67 protein, a cellular marker for proliferation, is another important prognostic factor. A European Mantle Cell network study showed that median overall survival for patients with a Ki-67 proliferation index of less than 30% was not reached, and 5-year survival was 75%. At the same time, the median overall survival (OS) for those with Ki-67 proliferation index of 30% or greater was just 3.4 years, and 5-year OS was only 41% (J Clin Oncol. 2016 Apr 20;34[12]:1386-94).

The prognostic effect was independent of induction treatment, Dr. Blum said.

Combining MIPI and the Ki-67 index (MIPI-C) provides further value in defining a very high-risk group; those with both high MIPI and high Ki-67 had a median overall survival of only 1.5 years, and those with both, but who were under age 65, had median OS of only 1.7 years.
 

Histology

Patients with blastoid MCL variants were shown in that same study to have median OS of about 2.8 years, compared with 8 years in those with nonblastoid variants. The 5-year OS and progression-free survival (PFS) for blastoid variants were 35% and 29%, respectively, and for nonblastoid variants were 68% and 44%, respectively.

“But when you look at this with respect to the Ki-67 – so those patients that were called nonblastoid, that had a high Ki-67 index – their median overall survival is still lower at 5 years,” she said, noting that median OS was not reached in blastic variant (low-Ki-67) patients. “So it seems like the prognostic effect of cytology is largely explained by the Ki-67 index.”

In terms of karyotype, several studies have shown that complex karyotype is associated with poorer outcomes. One recent multicenter study of 274 patients showed that median OS in 53 patients with at least three cytogenetic abnormalities versus the remaining patients was 4.5 years vs. 11.6 years, and median PFS was 1.9 vs. 4.4 years (Cancer. 2018 Jun 1;124[11]:2306-15).

TP53 deletions (which affect about 20% of MCL patients) and mutations (which affect about 10%), are also useful prognostic factors, she said, noting that each is associated with inferior outcomes, and in one study patients with both appeared to have the worst outcomes (Blood. 2017;130:1903-10).

Another study showed that high TP53 staining (greater than 50% positive) is also associated with inferior outcomes, including reduced time to treatment failure and lower overall survival (Blood. 2018;131:417-20).

Finally, the most important factor is the patient’s wishes, Dr. Blum said, noting that she has “a lot of long discussions with these patients.”

“I consider all of these factors with each patient that I see with mantle cell,” she said.

Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.

[email protected]