Mantle Cell Lymphoma

ATLANTA – More than one-fifth of patients with relapsed or refractory mantle cell lymphoma had a complete response to single-agent therapy with experimental ibrutinib, and another two-fifths had a partial response, investigators reported.

"Colleagues, this is the highest response rate ever reported, ever achieved by one single drug in the history of relapsed mantle cell lymphoma," Dr. Michael Wang told attendees at the annual meeting of the American Society of Hematology.

Dr. Wang’s evident excitement about the data came exactly 1 year to the day after he announced preliminary results of the phase II trial at ASH 2011. At that time, the drug was known only as PCI-32765.

Those early data showed that ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, induced complete response in 16% and partial response in 53% of patients evaluated at that time for a combined overall response rate of 69%.

The drug demonstrated efficacy against bulky disease, and its effects in early studies appeared to be independent of the MCL [Mantle Cell Lymphoma] International Prognostic Index (MIPI) score.

At this year’s meeting, Dr. Wang of the University of Texas M.D. Anderson Cancer Center, Houston, reported that in an efficacy cohort of 110 patients, 22% had a complete response and 46% a partial response. Among patients who had previously been treated with bortezomib (Velcade), 23% had a complete response, and 49% had a partial response. In bortezomib-naive patients the response rates were 21% and 44%, respectively.

At 9.2 months of follow-up (data cutoff Sept. 21, 2012), the median duration of response had not been reached. Median progression-free survival was 13.9 months.

Ibrutinib was well tolerated

BTK, an essential element of the B-cell antigen receptor–signaling pathway, is expressed in several hematologic malignancies, including lymphoma and chronic lymphocytic leukemia, for which positive clinical trial data were also presented at the meeting. Ibrutinib blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion. It has been shown in in vitro studies to block pERK, pJNK, and NF-KappaB pathways in MCL cell lines.

Dr. Wang and colleagues at 18 U.S. and European centers enrolled patients with confirmed overexpression of cyclin D1 or the 11;14 translocation and measurable disease. The patients had not been able to achieve at least a partial response to prior therapy, or had disease progression following their most recent treatment regimen. All had at least one, but not more than five prior lines of therapy, and adequate end-organ function, and Eastern Cooperative Oncology Group performance status of 2 or lower.

The drug was generally well tolerated, he said, with neutropenia, thrombocytopenia, and anemia being the most frequent hematologic toxicities, and diarrhea, fatigue, nausea, and respiratory tract infections being the most common nonhematologic adverse events.

Dr. Wang noted that longer follow-up of data on 51 patients in the cohort that he presented at ASH 2011 show improvement in complete response rates. The initial rates among bortezomib-naive, bortezomib experienced, and all patients were 16%, 15%, and 16%, respectively, at a median of 3.7 months. In the current follow-up of these patients, however (median 14.7 months), the complete response rates had improved to 40%, 38%, and 39%, respectively, with respective overall response rates of 77%, 71%, and 75%. He called the gradual increase in complete response rates the "phenomenon of incremental response."

Phenomenon of incremental response

Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center, New York, said after Dr. Wang’s presentation that the "phenomenon of incremental response" Dr. Wang described is not really a phenomenon at all.

"The reason you’re giving the drug continuously is that you expect to see a better response," he said. "It’s not unique to this drug, but in rituximab it’s seen when you stop the drug, in lenalidomide it’s seen when you stop the drug, and in radioimmunotherapy it’s seen when you stop the drug. So incremental response is a well described phenomenon in lymphomas," Dr. Zelenetz said.

"This has been just an interim analysis our data. We look forward to updating you with the final results of this clinical trial with excitement, caution, and confidence," Dr.Wang said.

The study was supported by Pharmacyclics. Dr. Wang is on the scientific advisory board of the company. Dr. Zelenetz had no relevant disclosures.

ATLANTA – More than one-fifth of patients with relapsed or refractory mantle cell lymphoma had a complete response to single-agent therapy with experimental ibrutinib, and another two-fifths had a partial response, investigators reported.

"Colleagues, this is the highest response rate ever reported, ever achieved by one single drug in the history of relapsed mantle cell lymphoma," Dr. Michael Wang told attendees at the annual meeting of the American Society of Hematology.

Dr. Wang’s evident excitement about the data came exactly 1 year to the day after he announced preliminary results of the phase II trial at ASH 2011. At that time, the drug was known only as PCI-32765.

Those early data showed that ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, induced complete response in 16% and partial response in 53% of patients evaluated at that time for a combined overall response rate of 69%.

The drug demonstrated efficacy against bulky disease, and its effects in early studies appeared to be independent of the MCL [Mantle Cell Lymphoma] International Prognostic Index (MIPI) score.

At this year’s meeting, Dr. Wang of the University of Texas M.D. Anderson Cancer Center, Houston, reported that in an efficacy cohort of 110 patients, 22% had a complete response and 46% a partial response. Among patients who had previously been treated with bortezomib (Velcade), 23% had a complete response, and 49% had a partial response. In bortezomib-naive patients the response rates were 21% and 44%, respectively.

At 9.2 months of follow-up (data cutoff Sept. 21, 2012), the median duration of response had not been reached. Median progression-free survival was 13.9 months.

Ibrutinib was well tolerated

BTK, an essential element of the B-cell antigen receptor–signaling pathway, is expressed in several hematologic malignancies, including lymphoma and chronic lymphocytic leukemia, for which positive clinical trial data were also presented at the meeting. Ibrutinib blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion. It has been shown in in vitro studies to block pERK, pJNK, and NF-KappaB pathways in MCL cell lines.

Dr. Wang and colleagues at 18 U.S. and European centers enrolled patients with confirmed overexpression of cyclin D1 or the 11;14 translocation and measurable disease. The patients had not been able to achieve at least a partial response to prior therapy, or had disease progression following their most recent treatment regimen. All had at least one, but not more than five prior lines of therapy, and adequate end-organ function, and Eastern Cooperative Oncology Group performance status of 2 or lower.

The drug was generally well tolerated, he said, with neutropenia, thrombocytopenia, and anemia being the most frequent hematologic toxicities, and diarrhea, fatigue, nausea, and respiratory tract infections being the most common nonhematologic adverse events.

Dr. Wang noted that longer follow-up of data on 51 patients in the cohort that he presented at ASH 2011 show improvement in complete response rates. The initial rates among bortezomib-naive, bortezomib experienced, and all patients were 16%, 15%, and 16%, respectively, at a median of 3.7 months. In the current follow-up of these patients, however (median 14.7 months), the complete response rates had improved to 40%, 38%, and 39%, respectively, with respective overall response rates of 77%, 71%, and 75%. He called the gradual increase in complete response rates the "phenomenon of incremental response."

Phenomenon of incremental response

Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center, New York, said after Dr. Wang’s presentation that the "phenomenon of incremental response" Dr. Wang described is not really a phenomenon at all.

"The reason you’re giving the drug continuously is that you expect to see a better response," he said. "It’s not unique to this drug, but in rituximab it’s seen when you stop the drug, in lenalidomide it’s seen when you stop the drug, and in radioimmunotherapy it’s seen when you stop the drug. So incremental response is a well described phenomenon in lymphomas," Dr. Zelenetz said.

"This has been just an interim analysis our data. We look forward to updating you with the final results of this clinical trial with excitement, caution, and confidence," Dr.Wang said.

The study was supported by Pharmacyclics. Dr. Wang is on the scientific advisory board of the company. Dr. Zelenetz had no relevant disclosures.

ATLANTA – More than one-fifth of patients with relapsed or refractory mantle cell lymphoma had a complete response to single-agent therapy with experimental ibrutinib, and another two-fifths had a partial response, investigators reported.

"Colleagues, this is the highest response rate ever reported, ever achieved by one single drug in the history of relapsed mantle cell lymphoma," Dr. Michael Wang told attendees at the annual meeting of the American Society of Hematology.

Dr. Wang’s evident excitement about the data came exactly 1 year to the day after he announced preliminary results of the phase II trial at ASH 2011. At that time, the drug was known only as PCI-32765.

Those early data showed that ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase (BTK) expressed in several hematologic malignancies, induced complete response in 16% and partial response in 53% of patients evaluated at that time for a combined overall response rate of 69%.

The drug demonstrated efficacy against bulky disease, and its effects in early studies appeared to be independent of the MCL [Mantle Cell Lymphoma] International Prognostic Index (MIPI) score.

At this year’s meeting, Dr. Wang of the University of Texas M.D. Anderson Cancer Center, Houston, reported that in an efficacy cohort of 110 patients, 22% had a complete response and 46% a partial response. Among patients who had previously been treated with bortezomib (Velcade), 23% had a complete response, and 49% had a partial response. In bortezomib-naive patients the response rates were 21% and 44%, respectively.

At 9.2 months of follow-up (data cutoff Sept. 21, 2012), the median duration of response had not been reached. Median progression-free survival was 13.9 months.

Ibrutinib was well tolerated

BTK, an essential element of the B-cell antigen receptor–signaling pathway, is expressed in several hematologic malignancies, including lymphoma and chronic lymphocytic leukemia, for which positive clinical trial data were also presented at the meeting. Ibrutinib blocks receptor signaling and induces apoptosis, as well as mantle cell migration and adhesion. It has been shown in in vitro studies to block pERK, pJNK, and NF-KappaB pathways in MCL cell lines.

Dr. Wang and colleagues at 18 U.S. and European centers enrolled patients with confirmed overexpression of cyclin D1 or the 11;14 translocation and measurable disease. The patients had not been able to achieve at least a partial response to prior therapy, or had disease progression following their most recent treatment regimen. All had at least one, but not more than five prior lines of therapy, and adequate end-organ function, and Eastern Cooperative Oncology Group performance status of 2 or lower.

The drug was generally well tolerated, he said, with neutropenia, thrombocytopenia, and anemia being the most frequent hematologic toxicities, and diarrhea, fatigue, nausea, and respiratory tract infections being the most common nonhematologic adverse events.

Dr. Wang noted that longer follow-up of data on 51 patients in the cohort that he presented at ASH 2011 show improvement in complete response rates. The initial rates among bortezomib-naive, bortezomib experienced, and all patients were 16%, 15%, and 16%, respectively, at a median of 3.7 months. In the current follow-up of these patients, however (median 14.7 months), the complete response rates had improved to 40%, 38%, and 39%, respectively, with respective overall response rates of 77%, 71%, and 75%. He called the gradual increase in complete response rates the "phenomenon of incremental response."

Phenomenon of incremental response

Dr. Andrew D. Zelenetz of Memorial Sloan-Kettering Cancer Center, New York, said after Dr. Wang’s presentation that the "phenomenon of incremental response" Dr. Wang described is not really a phenomenon at all.

"The reason you’re giving the drug continuously is that you expect to see a better response," he said. "It’s not unique to this drug, but in rituximab it’s seen when you stop the drug, in lenalidomide it’s seen when you stop the drug, and in radioimmunotherapy it’s seen when you stop the drug. So incremental response is a well described phenomenon in lymphomas," Dr. Zelenetz said.

"This has been just an interim analysis our data. We look forward to updating you with the final results of this clinical trial with excitement, caution, and confidence," Dr.Wang said.

The study was supported by Pharmacyclics. Dr. Wang is on the scientific advisory board of the company. Dr. Zelenetz had no relevant disclosures.

AMSTERDAM – Although it is rare and the prognosis for patients is often poor, the presence of central nervous system involvement at the time of diagnosis of mantle cell lymphoma is not always immediately fatal, according to findings from an international study.

According to the European Mantle Cell Lymphoma Network (EMCLN) findings, the crude prevalence of CNS events was 0.9% at the time of diagnosis and 4.1% at any time. The multicenter, retrospective study found that the median time to a CNS event’s occurring was 15.2 months, with an overall survival of 3.9 months after the event was identified, but some patients were still alive 2 years later.

"We now have some better descriptors about what the expectations and outcome of patients with central nervous system involvement are," Dr. John Seymour said in an interview at the annual congress of the European Hematology Association.

Dr. Seymour, professor and chair of the hematology service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria, added that even though the overall prognosis of patients who develop CNS involvement is very poor, there are some patients who do better than others.

There is "a subgroup [of patients] who are able to receive high-dose ara-c [cytarabine] or high-dose methotrexate treatment, who are young and fit enough, who do somewhat better," Dr. Seymour said. "A proportion will be alive at 2 years, so it’s not an inevitably, rapidly fatal, and ... futile situation."

Mantle cell lymphomas are a rare type of non-Hodgkin’s lymphoma (NHL), accounting for just less than 3% of all NHL cases in the United States and affecting primarily more elderly patients (Cancer 2008;113:791-8).CNS involvement is also a rare and often devastating event, but it has not previously been very well characterized. As a result, it’s not known whether CNS prophylaxis is of benefit to patients.

The aim of the EMCLN study, therefore, was to look at the problem in more detail, to determine the prevalence of CNS involvement, and to look for any clinically defining features, effect of treatment, and patient outcomes.

A retrospective database review by EMCLN members in 12 centers identified 1,396 patients with mantle cell lymphoma, of whom 1,339 had no CNS involvement. Of the 57 patients with CNS involvement, most (44) developed it at some point during the course of their follow-up.

At diagnosis of mantle cell lymphoma, the patients who developed CNS involvement had a median age of 61 years, but this ranged from 38 years to 82 years; patients were predominantly men (70%), with stage IV (91%) disease, and 28% had blastoid histology. Isolated CNS involvement occurred in 15 cases.

Prominent features were a high MIPI (Mantle Cell Lymphoma International Prognostic Index) score (61% of cases), a Ki-67 greater than 30% in 69% of patients, and increased beta₂-microglobulin and lactate dehydrogenase in 77% and 75% of cases, respectively. The bone marrow and the peripheral blood were the most common extranodal sites involved, affecting two or more sites in 61% of patients.

At diagnosis of CNS involvement, patients’ neurologic symptoms included weakness, altered mental state, headache, and ocular problems such as double vision. Other symptoms – such as sensory disturbances, pain, sciatica, dizziness, vertigo, ataxia, seizure, and dysphagia – occurred but were less frequent.

CSF cytology and flow cytometry showed a high sensitivity for identifying CNS involvement, with 85% having positive cytology and 91% a positive flow cytometry result.

"Patients had a range of chemotherapies prior to developing central nervous system involvement, but receipt of these regimens was not totally protective," Dr. Seymour said. Data were not collected to enable the relative risk of CNS development with the regimens received.

Chemotherapy was the most frequent treatment strategy to allay CNS disease (67%), and some patients did appear to achieve a complete remission of the CNS disease as a result. In an exploratory analysis, these patients also tended to have improved overall survival, as did those with lower white cell counts (less than 10.9 x 10⁹/L), and who received treatment with high-dose antimetabolites.

"In the longer term, these data will provide a foundation for us to identify predictive factors, to identify – ahead of the event – those people at increased risk," Dr. Seymour said, adding his hope that this will allow preventive steps to be taken.

Dr. Seymour had no conflicts of interest.

AMSTERDAM – Although it is rare and the prognosis for patients is often poor, the presence of central nervous system involvement at the time of diagnosis of mantle cell lymphoma is not always immediately fatal, according to findings from an international study.

According to the European Mantle Cell Lymphoma Network (EMCLN) findings, the crude prevalence of CNS events was 0.9% at the time of diagnosis and 4.1% at any time. The multicenter, retrospective study found that the median time to a CNS event’s occurring was 15.2 months, with an overall survival of 3.9 months after the event was identified, but some patients were still alive 2 years later.

"We now have some better descriptors about what the expectations and outcome of patients with central nervous system involvement are," Dr. John Seymour said in an interview at the annual congress of the European Hematology Association.

Dr. Seymour, professor and chair of the hematology service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria, added that even though the overall prognosis of patients who develop CNS involvement is very poor, there are some patients who do better than others.

There is "a subgroup [of patients] who are able to receive high-dose ara-c [cytarabine] or high-dose methotrexate treatment, who are young and fit enough, who do somewhat better," Dr. Seymour said. "A proportion will be alive at 2 years, so it’s not an inevitably, rapidly fatal, and ... futile situation."

Mantle cell lymphomas are a rare type of non-Hodgkin’s lymphoma (NHL), accounting for just less than 3% of all NHL cases in the United States and affecting primarily more elderly patients (Cancer 2008;113:791-8).CNS involvement is also a rare and often devastating event, but it has not previously been very well characterized. As a result, it’s not known whether CNS prophylaxis is of benefit to patients.

The aim of the EMCLN study, therefore, was to look at the problem in more detail, to determine the prevalence of CNS involvement, and to look for any clinically defining features, effect of treatment, and patient outcomes.

A retrospective database review by EMCLN members in 12 centers identified 1,396 patients with mantle cell lymphoma, of whom 1,339 had no CNS involvement. Of the 57 patients with CNS involvement, most (44) developed it at some point during the course of their follow-up.

At diagnosis of mantle cell lymphoma, the patients who developed CNS involvement had a median age of 61 years, but this ranged from 38 years to 82 years; patients were predominantly men (70%), with stage IV (91%) disease, and 28% had blastoid histology. Isolated CNS involvement occurred in 15 cases.

Prominent features were a high MIPI (Mantle Cell Lymphoma International Prognostic Index) score (61% of cases), a Ki-67 greater than 30% in 69% of patients, and increased beta₂-microglobulin and lactate dehydrogenase in 77% and 75% of cases, respectively. The bone marrow and the peripheral blood were the most common extranodal sites involved, affecting two or more sites in 61% of patients.

At diagnosis of CNS involvement, patients’ neurologic symptoms included weakness, altered mental state, headache, and ocular problems such as double vision. Other symptoms – such as sensory disturbances, pain, sciatica, dizziness, vertigo, ataxia, seizure, and dysphagia – occurred but were less frequent.

CSF cytology and flow cytometry showed a high sensitivity for identifying CNS involvement, with 85% having positive cytology and 91% a positive flow cytometry result.

"Patients had a range of chemotherapies prior to developing central nervous system involvement, but receipt of these regimens was not totally protective," Dr. Seymour said. Data were not collected to enable the relative risk of CNS development with the regimens received.

Chemotherapy was the most frequent treatment strategy to allay CNS disease (67%), and some patients did appear to achieve a complete remission of the CNS disease as a result. In an exploratory analysis, these patients also tended to have improved overall survival, as did those with lower white cell counts (less than 10.9 x 10⁹/L), and who received treatment with high-dose antimetabolites.

"In the longer term, these data will provide a foundation for us to identify predictive factors, to identify – ahead of the event – those people at increased risk," Dr. Seymour said, adding his hope that this will allow preventive steps to be taken.

Dr. Seymour had no conflicts of interest.

AMSTERDAM – Although it is rare and the prognosis for patients is often poor, the presence of central nervous system involvement at the time of diagnosis of mantle cell lymphoma is not always immediately fatal, according to findings from an international study.

According to the European Mantle Cell Lymphoma Network (EMCLN) findings, the crude prevalence of CNS events was 0.9% at the time of diagnosis and 4.1% at any time. The multicenter, retrospective study found that the median time to a CNS event’s occurring was 15.2 months, with an overall survival of 3.9 months after the event was identified, but some patients were still alive 2 years later.

"We now have some better descriptors about what the expectations and outcome of patients with central nervous system involvement are," Dr. John Seymour said in an interview at the annual congress of the European Hematology Association.

Dr. Seymour, professor and chair of the hematology service at Australia’s Peter MacCallum Cancer Centre in East Melbourne, Victoria, added that even though the overall prognosis of patients who develop CNS involvement is very poor, there are some patients who do better than others.

There is "a subgroup [of patients] who are able to receive high-dose ara-c [cytarabine] or high-dose methotrexate treatment, who are young and fit enough, who do somewhat better," Dr. Seymour said. "A proportion will be alive at 2 years, so it’s not an inevitably, rapidly fatal, and ... futile situation."

Mantle cell lymphomas are a rare type of non-Hodgkin’s lymphoma (NHL), accounting for just less than 3% of all NHL cases in the United States and affecting primarily more elderly patients (Cancer 2008;113:791-8).CNS involvement is also a rare and often devastating event, but it has not previously been very well characterized. As a result, it’s not known whether CNS prophylaxis is of benefit to patients.

The aim of the EMCLN study, therefore, was to look at the problem in more detail, to determine the prevalence of CNS involvement, and to look for any clinically defining features, effect of treatment, and patient outcomes.

A retrospective database review by EMCLN members in 12 centers identified 1,396 patients with mantle cell lymphoma, of whom 1,339 had no CNS involvement. Of the 57 patients with CNS involvement, most (44) developed it at some point during the course of their follow-up.

At diagnosis of mantle cell lymphoma, the patients who developed CNS involvement had a median age of 61 years, but this ranged from 38 years to 82 years; patients were predominantly men (70%), with stage IV (91%) disease, and 28% had blastoid histology. Isolated CNS involvement occurred in 15 cases.

Prominent features were a high MIPI (Mantle Cell Lymphoma International Prognostic Index) score (61% of cases), a Ki-67 greater than 30% in 69% of patients, and increased beta₂-microglobulin and lactate dehydrogenase in 77% and 75% of cases, respectively. The bone marrow and the peripheral blood were the most common extranodal sites involved, affecting two or more sites in 61% of patients.

At diagnosis of CNS involvement, patients’ neurologic symptoms included weakness, altered mental state, headache, and ocular problems such as double vision. Other symptoms – such as sensory disturbances, pain, sciatica, dizziness, vertigo, ataxia, seizure, and dysphagia – occurred but were less frequent.

CSF cytology and flow cytometry showed a high sensitivity for identifying CNS involvement, with 85% having positive cytology and 91% a positive flow cytometry result.

"Patients had a range of chemotherapies prior to developing central nervous system involvement, but receipt of these regimens was not totally protective," Dr. Seymour said. Data were not collected to enable the relative risk of CNS development with the regimens received.

Chemotherapy was the most frequent treatment strategy to allay CNS disease (67%), and some patients did appear to achieve a complete remission of the CNS disease as a result. In an exploratory analysis, these patients also tended to have improved overall survival, as did those with lower white cell counts (less than 10.9 x 10⁹/L), and who received treatment with high-dose antimetabolites.

"In the longer term, these data will provide a foundation for us to identify predictive factors, to identify – ahead of the event – those people at increased risk," Dr. Seymour said, adding his hope that this will allow preventive steps to be taken.

Dr. Seymour had no conflicts of interest.