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Targeting new myeloma pathway pays off with ARRY-520
ATLANTA – The experimental drug ARRY-520, the first kinesin spindle protein inhibitor in multiple myeloma, prompted responses in nearly one-fourth of heavily pretreated and triple-refractory patients in a phase II study.
The overall response rate to single-agent ARRY-520 was 16% in patients with a median of six prior regimens. It reached 22% when combined with dexamethasone in patients with a median of 10 prior regimens – all but one of whom was refractory to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Decadron), Dr. Jatin Shah reported at the annual meeting of the American Society of Hematology.
Kinesin spindle protein (KSP) is a microtubule motor protein required for mitosis and separation of the mitotic spindle pole into a bipolar spindle pole. Inhibition of KSP prevents formation of the bipolar spindle, leading to cell death. Preclinical work shows that ARRY-520 also down-regulates myeloid cell leukemia-1 levels, a mechanism for dexamethasone resistance.
The investigators also identified a potential biomarker called alpha 1-acid glycoprotein (AAG) that may predict how well patients respond to ARRY-520.
Selecting patients by AAG serum results increased the response rate to 33% in the combination group, a population with an unmet clinical need, said Dr. Shah of the University of Texas M.D. Anderson Cancer Center in Houston.
"The assay isn’t a fancy test; it can be done actually at any commercial lab," he said in an interview. "The key is to validate that the labs are doing the assay in the same way."
Duration of response noted
Dr. Antonio Palumbo, chief of the myeloma unit at the University Hospital of Torino, Italy, who comoderated the session, said in an interview that ARRY-520 is "certainly an exciting new agent" in multiple myeloma, given its novel therapeutic target, partial responses of 20%-30% in such advanced disease and a potential biomarker.
"I think the biomarker was important and probably also the durability because this type of drug may have a major role in durability, more than on response," he said.
Median duration of response was 8.6 months with ARRY-520 monotherapy (range 1.4-20 months) and 5.4 months with combination therapy (2.5-9 months).
Dr. Angela Dispenzieri, hematologist and professor of medicine at Mayo Clinic, Rochester, Minn., and a member of the meeting’s scientific committee, was more effusive in her assessment of the results.
"Actually, I think it’s the best thing so far at ASH," she said after the session on the penultimate day of the meeting. "It’s novel.
"This is a new class and it actually has single-agent activity. That’s the beginning and that is very important. I was really impressed, and I’m really cynical."
Both Dr. Dispenzieri and Dr. Palumbo said results should be better if ARRY-520 is combined with other agents such as bortezomib, proteasome inhibitors or immunomodulatory drugs (IMiDs).
Preliminary results reported in a poster at the meeting show that one of six evaluable patients achieved a near complete response and four had stable disease after completing at least one cycle of ARRY-520 plus the proteasome inhibitor carfilzomib (Kyprolis), Dr. Shah reported.
"We’re already starting to see a signal there, and we’re going to go with IMiDs next," he said.
A phase Ib combination trial with bortezomib is also underway.
Fifty patients in two cohorts
The current phase II study included 32 patients who received single-agent ARRY-520 at 1.5 mg/m2 on days 1 and 2 every 2 weeks and 18 patients who also received low-dose dexamethasone 40 mg once weekly. Both groups received granulocyte–colony stimulating factor support.
The first cohort had relapsed and/or refractory multiple myeloma after receiving at least two prior rounds of therapy (range 2-19) that included bortezomib and an IMiD. Roughly half were bortezomib refractory (53%) and 41% were triple refractory.
Cohort two had also received at least two prior regimens (range 5-13), but progressed during or within 60 days of their last regimen, was refractory to lenalidomide, bortezomib, and dexamethasone (except one dexamethasone-refractory patient) and had received adequate prior alkylator therapy. High-risk cytogenetics were present in 17% vs. 9% of cohort one.
In cohort one, there were 5 partial responses, 6 minor plus partial responses, and 14 cases of stable disease, Dr. Shah said. The median time to response was 4.4 months and median progression-free survival was 3.7 months. The cohort had very durable responses at a median of 8.6 months (range 1.4-20 months), and an overall survival of 19 months, he said.
In cohort two, there were 4 partial responses, 6 minimal plus partial responses and 5 patients with stable disease. The median time on treatment about doubled from 2.1 in cohort one to 3.9 months, with a shorter time to response of 3.4 months. The median duration of response was shorter at 5.4 months, "but again this was a very different patient population," Dr. Shah said.
An analysis of baseline AAG levels in 45 patients revealed that patients with low AAG remained on study longer than did those with high AAG in both cohort one (3.4 months vs. 1.7 months) and cohort two (6.2 months vs. 1.6 months). Moreover, 24% of low-AAG patients on monotherapy and 22% on combination therapy achieved at least a partial response, whereas no patient with high AAG levels did so.
In vitro work has shown that increasing levels of AAG result in increased half maximal inhibitory concentration (IC50) of ARRY-520, suggesting that patients with elevated AAG may have subtherapeutic exposure to the drug, Dr. Shah explained. AAG does not bind to other standard multiple myeloma agents on the market, and is not correlated with prognostic markers in myeloma.
Nonhematologic adverse events were very low, including one case each of grade 4 fatigue and hypokalemia, and two cases of grade 4 pneumonia.
As expected from the biology of the drug, grade 3/4 hematologic events were more common, but generally reversible and not observed to be cumulative out to 3 years of therapy, Dr. Shah said. Grade 4 neutropenia, thrombocytopenia, and anemia were present in 28%, 25%, and 6% of patients in cohort one and in 38%, 19% and 5% of cohort two, respectively. Febrile neutropenia was grade 3 only, and reported in just one patient in each group, he noted.
Dr. Shah and coauthors reported relationships with study sponsor Array BioPharma, which is developing ARRY-520. Dr. Palumbo disclosed relationships with other companies.
Dr. Antonio Palumbo,
ATLANTA – The experimental drug ARRY-520, the first kinesin spindle protein inhibitor in multiple myeloma, prompted responses in nearly one-fourth of heavily pretreated and triple-refractory patients in a phase II study.
The overall response rate to single-agent ARRY-520 was 16% in patients with a median of six prior regimens. It reached 22% when combined with dexamethasone in patients with a median of 10 prior regimens – all but one of whom was refractory to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Decadron), Dr. Jatin Shah reported at the annual meeting of the American Society of Hematology.
Kinesin spindle protein (KSP) is a microtubule motor protein required for mitosis and separation of the mitotic spindle pole into a bipolar spindle pole. Inhibition of KSP prevents formation of the bipolar spindle, leading to cell death. Preclinical work shows that ARRY-520 also down-regulates myeloid cell leukemia-1 levels, a mechanism for dexamethasone resistance.
The investigators also identified a potential biomarker called alpha 1-acid glycoprotein (AAG) that may predict how well patients respond to ARRY-520.
Selecting patients by AAG serum results increased the response rate to 33% in the combination group, a population with an unmet clinical need, said Dr. Shah of the University of Texas M.D. Anderson Cancer Center in Houston.
"The assay isn’t a fancy test; it can be done actually at any commercial lab," he said in an interview. "The key is to validate that the labs are doing the assay in the same way."
Duration of response noted
Dr. Antonio Palumbo, chief of the myeloma unit at the University Hospital of Torino, Italy, who comoderated the session, said in an interview that ARRY-520 is "certainly an exciting new agent" in multiple myeloma, given its novel therapeutic target, partial responses of 20%-30% in such advanced disease and a potential biomarker.
"I think the biomarker was important and probably also the durability because this type of drug may have a major role in durability, more than on response," he said.
Median duration of response was 8.6 months with ARRY-520 monotherapy (range 1.4-20 months) and 5.4 months with combination therapy (2.5-9 months).
Dr. Angela Dispenzieri, hematologist and professor of medicine at Mayo Clinic, Rochester, Minn., and a member of the meeting’s scientific committee, was more effusive in her assessment of the results.
"Actually, I think it’s the best thing so far at ASH," she said after the session on the penultimate day of the meeting. "It’s novel.
"This is a new class and it actually has single-agent activity. That’s the beginning and that is very important. I was really impressed, and I’m really cynical."
Both Dr. Dispenzieri and Dr. Palumbo said results should be better if ARRY-520 is combined with other agents such as bortezomib, proteasome inhibitors or immunomodulatory drugs (IMiDs).
Preliminary results reported in a poster at the meeting show that one of six evaluable patients achieved a near complete response and four had stable disease after completing at least one cycle of ARRY-520 plus the proteasome inhibitor carfilzomib (Kyprolis), Dr. Shah reported.
"We’re already starting to see a signal there, and we’re going to go with IMiDs next," he said.
A phase Ib combination trial with bortezomib is also underway.
Fifty patients in two cohorts
The current phase II study included 32 patients who received single-agent ARRY-520 at 1.5 mg/m2 on days 1 and 2 every 2 weeks and 18 patients who also received low-dose dexamethasone 40 mg once weekly. Both groups received granulocyte–colony stimulating factor support.
The first cohort had relapsed and/or refractory multiple myeloma after receiving at least two prior rounds of therapy (range 2-19) that included bortezomib and an IMiD. Roughly half were bortezomib refractory (53%) and 41% were triple refractory.
Cohort two had also received at least two prior regimens (range 5-13), but progressed during or within 60 days of their last regimen, was refractory to lenalidomide, bortezomib, and dexamethasone (except one dexamethasone-refractory patient) and had received adequate prior alkylator therapy. High-risk cytogenetics were present in 17% vs. 9% of cohort one.
In cohort one, there were 5 partial responses, 6 minor plus partial responses, and 14 cases of stable disease, Dr. Shah said. The median time to response was 4.4 months and median progression-free survival was 3.7 months. The cohort had very durable responses at a median of 8.6 months (range 1.4-20 months), and an overall survival of 19 months, he said.
In cohort two, there were 4 partial responses, 6 minimal plus partial responses and 5 patients with stable disease. The median time on treatment about doubled from 2.1 in cohort one to 3.9 months, with a shorter time to response of 3.4 months. The median duration of response was shorter at 5.4 months, "but again this was a very different patient population," Dr. Shah said.
An analysis of baseline AAG levels in 45 patients revealed that patients with low AAG remained on study longer than did those with high AAG in both cohort one (3.4 months vs. 1.7 months) and cohort two (6.2 months vs. 1.6 months). Moreover, 24% of low-AAG patients on monotherapy and 22% on combination therapy achieved at least a partial response, whereas no patient with high AAG levels did so.
In vitro work has shown that increasing levels of AAG result in increased half maximal inhibitory concentration (IC50) of ARRY-520, suggesting that patients with elevated AAG may have subtherapeutic exposure to the drug, Dr. Shah explained. AAG does not bind to other standard multiple myeloma agents on the market, and is not correlated with prognostic markers in myeloma.
Nonhematologic adverse events were very low, including one case each of grade 4 fatigue and hypokalemia, and two cases of grade 4 pneumonia.
As expected from the biology of the drug, grade 3/4 hematologic events were more common, but generally reversible and not observed to be cumulative out to 3 years of therapy, Dr. Shah said. Grade 4 neutropenia, thrombocytopenia, and anemia were present in 28%, 25%, and 6% of patients in cohort one and in 38%, 19% and 5% of cohort two, respectively. Febrile neutropenia was grade 3 only, and reported in just one patient in each group, he noted.
Dr. Shah and coauthors reported relationships with study sponsor Array BioPharma, which is developing ARRY-520. Dr. Palumbo disclosed relationships with other companies.
ATLANTA – The experimental drug ARRY-520, the first kinesin spindle protein inhibitor in multiple myeloma, prompted responses in nearly one-fourth of heavily pretreated and triple-refractory patients in a phase II study.
The overall response rate to single-agent ARRY-520 was 16% in patients with a median of six prior regimens. It reached 22% when combined with dexamethasone in patients with a median of 10 prior regimens – all but one of whom was refractory to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Decadron), Dr. Jatin Shah reported at the annual meeting of the American Society of Hematology.
Kinesin spindle protein (KSP) is a microtubule motor protein required for mitosis and separation of the mitotic spindle pole into a bipolar spindle pole. Inhibition of KSP prevents formation of the bipolar spindle, leading to cell death. Preclinical work shows that ARRY-520 also down-regulates myeloid cell leukemia-1 levels, a mechanism for dexamethasone resistance.
The investigators also identified a potential biomarker called alpha 1-acid glycoprotein (AAG) that may predict how well patients respond to ARRY-520.
Selecting patients by AAG serum results increased the response rate to 33% in the combination group, a population with an unmet clinical need, said Dr. Shah of the University of Texas M.D. Anderson Cancer Center in Houston.
"The assay isn’t a fancy test; it can be done actually at any commercial lab," he said in an interview. "The key is to validate that the labs are doing the assay in the same way."
Duration of response noted
Dr. Antonio Palumbo, chief of the myeloma unit at the University Hospital of Torino, Italy, who comoderated the session, said in an interview that ARRY-520 is "certainly an exciting new agent" in multiple myeloma, given its novel therapeutic target, partial responses of 20%-30% in such advanced disease and a potential biomarker.
"I think the biomarker was important and probably also the durability because this type of drug may have a major role in durability, more than on response," he said.
Median duration of response was 8.6 months with ARRY-520 monotherapy (range 1.4-20 months) and 5.4 months with combination therapy (2.5-9 months).
Dr. Angela Dispenzieri, hematologist and professor of medicine at Mayo Clinic, Rochester, Minn., and a member of the meeting’s scientific committee, was more effusive in her assessment of the results.
"Actually, I think it’s the best thing so far at ASH," she said after the session on the penultimate day of the meeting. "It’s novel.
"This is a new class and it actually has single-agent activity. That’s the beginning and that is very important. I was really impressed, and I’m really cynical."
Both Dr. Dispenzieri and Dr. Palumbo said results should be better if ARRY-520 is combined with other agents such as bortezomib, proteasome inhibitors or immunomodulatory drugs (IMiDs).
Preliminary results reported in a poster at the meeting show that one of six evaluable patients achieved a near complete response and four had stable disease after completing at least one cycle of ARRY-520 plus the proteasome inhibitor carfilzomib (Kyprolis), Dr. Shah reported.
"We’re already starting to see a signal there, and we’re going to go with IMiDs next," he said.
A phase Ib combination trial with bortezomib is also underway.
Fifty patients in two cohorts
The current phase II study included 32 patients who received single-agent ARRY-520 at 1.5 mg/m2 on days 1 and 2 every 2 weeks and 18 patients who also received low-dose dexamethasone 40 mg once weekly. Both groups received granulocyte–colony stimulating factor support.
The first cohort had relapsed and/or refractory multiple myeloma after receiving at least two prior rounds of therapy (range 2-19) that included bortezomib and an IMiD. Roughly half were bortezomib refractory (53%) and 41% were triple refractory.
Cohort two had also received at least two prior regimens (range 5-13), but progressed during or within 60 days of their last regimen, was refractory to lenalidomide, bortezomib, and dexamethasone (except one dexamethasone-refractory patient) and had received adequate prior alkylator therapy. High-risk cytogenetics were present in 17% vs. 9% of cohort one.
In cohort one, there were 5 partial responses, 6 minor plus partial responses, and 14 cases of stable disease, Dr. Shah said. The median time to response was 4.4 months and median progression-free survival was 3.7 months. The cohort had very durable responses at a median of 8.6 months (range 1.4-20 months), and an overall survival of 19 months, he said.
In cohort two, there were 4 partial responses, 6 minimal plus partial responses and 5 patients with stable disease. The median time on treatment about doubled from 2.1 in cohort one to 3.9 months, with a shorter time to response of 3.4 months. The median duration of response was shorter at 5.4 months, "but again this was a very different patient population," Dr. Shah said.
An analysis of baseline AAG levels in 45 patients revealed that patients with low AAG remained on study longer than did those with high AAG in both cohort one (3.4 months vs. 1.7 months) and cohort two (6.2 months vs. 1.6 months). Moreover, 24% of low-AAG patients on monotherapy and 22% on combination therapy achieved at least a partial response, whereas no patient with high AAG levels did so.
In vitro work has shown that increasing levels of AAG result in increased half maximal inhibitory concentration (IC50) of ARRY-520, suggesting that patients with elevated AAG may have subtherapeutic exposure to the drug, Dr. Shah explained. AAG does not bind to other standard multiple myeloma agents on the market, and is not correlated with prognostic markers in myeloma.
Nonhematologic adverse events were very low, including one case each of grade 4 fatigue and hypokalemia, and two cases of grade 4 pneumonia.
As expected from the biology of the drug, grade 3/4 hematologic events were more common, but generally reversible and not observed to be cumulative out to 3 years of therapy, Dr. Shah said. Grade 4 neutropenia, thrombocytopenia, and anemia were present in 28%, 25%, and 6% of patients in cohort one and in 38%, 19% and 5% of cohort two, respectively. Febrile neutropenia was grade 3 only, and reported in just one patient in each group, he noted.
Dr. Shah and coauthors reported relationships with study sponsor Array BioPharma, which is developing ARRY-520. Dr. Palumbo disclosed relationships with other companies.
Dr. Antonio Palumbo,
Dr. Antonio Palumbo,
AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY
Major Finding: The overall response rate to single-agent ARRY-520 was 16% in patients with a median of 6 prior regimens and 22% when combined with dexamethasone in patients with a median of 10 prior regimens.
Data Source: Phase II study of ARRY-520 mono and combination therapy.
Disclosures: Dr. Shah and coauthors reported relationships with study sponsor Array BioPharma, which is developing ARRY-520. Dr. Palumbo disclosed relationships with other companies.
ASH12: New Myeloma Drug Works Better with Low-Dose Dexamethasone
Pomalidomide, an investigational third-generation immunomodulatory drug, was more effective when combined with low-dose dexamethasone than high-dose in a clinical trial presented at the annual meeting of the American Society of Hematology.
Patrice Wendling interviewed Dr. Meletios A. Dimopoulos on why reducing toxicity is important in multiple myeloma regimens.
Pomalidomide, an investigational third-generation immunomodulatory drug, was more effective when combined with low-dose dexamethasone than high-dose in a clinical trial presented at the annual meeting of the American Society of Hematology.
Patrice Wendling interviewed Dr. Meletios A. Dimopoulos on why reducing toxicity is important in multiple myeloma regimens.
Pomalidomide, an investigational third-generation immunomodulatory drug, was more effective when combined with low-dose dexamethasone than high-dose in a clinical trial presented at the annual meeting of the American Society of Hematology.
Patrice Wendling interviewed Dr. Meletios A. Dimopoulos on why reducing toxicity is important in multiple myeloma regimens.
ASH12: New Proteasome Inhibitor Shines In All-Oral Myeloma Regimen
Experimental MLN9708 is the first oral proteasome inhibitor, and it has shown itself to be highly active in a phase I/II clinical trial that enrolled 65 patients with newly diagnosed multiple myeloma.
Investigators reported that 92% responded to an all-oral regimen combining MLN9708 with lenalidomide (Revlimid) and dexamethsone. This included 55% with at least a very good partial response and 23% in complete response. A phase III trial is planned
Patrice Wendling interviewed Dr. Shaji K. Kumar on findings he presented at the annual meeting of the American Society of Hematology.
Experimental MLN9708 is the first oral proteasome inhibitor, and it has shown itself to be highly active in a phase I/II clinical trial that enrolled 65 patients with newly diagnosed multiple myeloma.
Investigators reported that 92% responded to an all-oral regimen combining MLN9708 with lenalidomide (Revlimid) and dexamethsone. This included 55% with at least a very good partial response and 23% in complete response. A phase III trial is planned
Patrice Wendling interviewed Dr. Shaji K. Kumar on findings he presented at the annual meeting of the American Society of Hematology.
Experimental MLN9708 is the first oral proteasome inhibitor, and it has shown itself to be highly active in a phase I/II clinical trial that enrolled 65 patients with newly diagnosed multiple myeloma.
Investigators reported that 92% responded to an all-oral regimen combining MLN9708 with lenalidomide (Revlimid) and dexamethsone. This included 55% with at least a very good partial response and 23% in complete response. A phase III trial is planned
Patrice Wendling interviewed Dr. Shaji K. Kumar on findings he presented at the annual meeting of the American Society of Hematology.
Experimental Ibrutinib Could Change Treatment of CLL
ATLANTA – The experimental oral therapy ibrutinib produces dramatic responses but dodges the significant toxicity seen in conventional treatments for chronic lymphocytic leukemia and small lymphocytic lymphoma.
In one of two phase II trials, the overall response rate was 68% in previously untreated patients and 71% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
The outcome was similar in patients with high-risk relapsed or refractory disease, with the possible exception of those with chromosome 17p deletion. However, with more than half responding, these patients still do better with ibrutinib than with any other therapy explored to date, said Dr. John C. Byrd, director of hematology at Ohio State Comprehensive Cancer Center in Columbus.
"Ibrutinib offers great potential to significantly change the treatment landscape of CLL," he said at a press briefing at the annual meeting of the American Society of Hematology.
In the second trial, combining ibrutinib with the anti-CD20 antibody rituximab (Rituxan) pushed the overall response rate to 83% in high-risk CLL and SLL, said Dr. Jan A. Burger, of the University of Texas M.D. Anderson Cancer Center in Houston.
He noted that several ongoing phase III trials are underway that should accelerate the development of ibrutinib for high-risk patients, who have a high unmet need for alternative treatments.
Ibrutinib is currently not available, even under compassionate use. Despite this, the drug is generating much enthusiasm among clinicians and patients, with some traveling great distances to get into these ongoing trials despite only a 50-50 chance of receiving the drug, said press briefing moderator Dr. Claire Dearden, head of the CLL unit at the Royal Marsden NHS Foundation Trust in London.
"It’s orally active, it’s well tolerated, it’s not chemo, and it produces excellent responses, particularly in patients who are elderly and frail and not necessarily suitable for the more intensive chemotherapy regimens that have become the first-line treatment for the younger, fitter patients," she said.
Ibrutinib, formerly known as PCI-32765, is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK) to enter clinical development. BTK is essential for B-cell receptor signaling, chemokine-mediated migration and adhesion, and toll-like receptor signaling.
96% Survival Estimates at 22 Months
Dr. Byrd reported new and updated results from 31 patients with treatment naive CLL or SLL, 61 with relapsed or refractory disease, and 24 with high-risk relapsed or refractory disease (defined as progression within 24 months of starting a regimen containing at least a nucleoside analogue or bendamustine in combination with a monoclonal antibody or failure to respond to such a regimen).
Patients were given ibrutinib 420 mg or 840 mg daily 2 hours before food until disease progression or intolerable toxicity. Their median age was 72.
After follow-up ranging from 14.7 months to 22.1 months, complete responses occurred in 10% of treatment-naive patients and 2% of relapsed or refractory patients, Dr. Byrd said. Partial responses occurred in 58% and 68%.
At 22 months, progression-free and overall survival estimates were both 96% among previously untreated patients. To put these results in perspective, he said, that with standard cytotoxic chemotherapy, one would expect this number to be 70% or less if patients are young and 50% or less if elderly. "So these are really dramatic results," he added.
In the relapsed or refractory group, progression-free survival was 76% and overall survival 85%.
Longer follow-up is needed to determine whether the remissions are durable once ibrutinib is stopped – something currently being studied more than a decade after clinicians began using another kinase inhibitor, imatinib (Gleevec), to treat chronic myeloid leukemia, Dr. Byrd said.
He reported 3 grade 3 and no grade 4 infections in treatment-naive patients, and 26 grade 3 infections and 4 grade 4 events in relapsed/refractory patients.
Nearly All Still on Study in Combination Trial
In the second trial, 40 patients received continuous ibrutinib 420 mg daily plus weekly rituximab 365 mg/m2 for 4 weeks, followed by daily ibrutinib plus monthly rituximab until month 6, followed by single-agent ibrutinib. High-risk CLL/SLL was defined as deletion 17p, TP53 mutation, deletion 11q, or less than 3 years remission after first-line chemo-immunotherapy. More than half of patients (58%) had stage IV disease.
After 3-6 months’ follow-up, there were 1 complete response, 32 partial responses, and 3 partial responses with lymphocytosis, Dr. Burger said. In all, 84% of patients experienced more than a 50% reduction in lymph node size.
At the time of the analysis, 95% of all patients and 90% with del 17p continued on therapy without disease progression.
Two patients came off study; one with pneumonia and an intracranial abscess, who died, and another who discontinued due to mucositis/ulcers after four cycles.
Severe toxicities were uncommon in both studies, particularly the considerable immunosuppression and serious infections associated with standard chemo-immunotherapy, the investigators said. The most common event was diarrhea, which was experienced by 54% of patients receiving ibrutinib monotherapy and was largely grade 1 or 2 and resolved after the first couple of cycles, Dr. Byrd said.
Other events included fatigue (29%), upper respiratory infection (29%), rash (28%), nausea (26%) and bone pain (25%). Rates were similar in the combination therapy trial, with bruising also seen in both trials
One of the ongoing phase III trials is the 350-patient RESONATE study evaluating ibrutinib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL or SLL.
Dr. Byrd disclosed research funding from the study sponsor Pharmacyclics, which is developing ibrutinib. Dr. Burger reported consulting for and research funding from Pharmacyclics. Co-authors of both studies are Pharmacyclics employees. Dr. Dearden disclosed no conflicts of interest.
ATLANTA – The experimental oral therapy ibrutinib produces dramatic responses but dodges the significant toxicity seen in conventional treatments for chronic lymphocytic leukemia and small lymphocytic lymphoma.
In one of two phase II trials, the overall response rate was 68% in previously untreated patients and 71% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
The outcome was similar in patients with high-risk relapsed or refractory disease, with the possible exception of those with chromosome 17p deletion. However, with more than half responding, these patients still do better with ibrutinib than with any other therapy explored to date, said Dr. John C. Byrd, director of hematology at Ohio State Comprehensive Cancer Center in Columbus.
"Ibrutinib offers great potential to significantly change the treatment landscape of CLL," he said at a press briefing at the annual meeting of the American Society of Hematology.
In the second trial, combining ibrutinib with the anti-CD20 antibody rituximab (Rituxan) pushed the overall response rate to 83% in high-risk CLL and SLL, said Dr. Jan A. Burger, of the University of Texas M.D. Anderson Cancer Center in Houston.
He noted that several ongoing phase III trials are underway that should accelerate the development of ibrutinib for high-risk patients, who have a high unmet need for alternative treatments.
Ibrutinib is currently not available, even under compassionate use. Despite this, the drug is generating much enthusiasm among clinicians and patients, with some traveling great distances to get into these ongoing trials despite only a 50-50 chance of receiving the drug, said press briefing moderator Dr. Claire Dearden, head of the CLL unit at the Royal Marsden NHS Foundation Trust in London.
"It’s orally active, it’s well tolerated, it’s not chemo, and it produces excellent responses, particularly in patients who are elderly and frail and not necessarily suitable for the more intensive chemotherapy regimens that have become the first-line treatment for the younger, fitter patients," she said.
Ibrutinib, formerly known as PCI-32765, is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK) to enter clinical development. BTK is essential for B-cell receptor signaling, chemokine-mediated migration and adhesion, and toll-like receptor signaling.
96% Survival Estimates at 22 Months
Dr. Byrd reported new and updated results from 31 patients with treatment naive CLL or SLL, 61 with relapsed or refractory disease, and 24 with high-risk relapsed or refractory disease (defined as progression within 24 months of starting a regimen containing at least a nucleoside analogue or bendamustine in combination with a monoclonal antibody or failure to respond to such a regimen).
Patients were given ibrutinib 420 mg or 840 mg daily 2 hours before food until disease progression or intolerable toxicity. Their median age was 72.
After follow-up ranging from 14.7 months to 22.1 months, complete responses occurred in 10% of treatment-naive patients and 2% of relapsed or refractory patients, Dr. Byrd said. Partial responses occurred in 58% and 68%.
At 22 months, progression-free and overall survival estimates were both 96% among previously untreated patients. To put these results in perspective, he said, that with standard cytotoxic chemotherapy, one would expect this number to be 70% or less if patients are young and 50% or less if elderly. "So these are really dramatic results," he added.
In the relapsed or refractory group, progression-free survival was 76% and overall survival 85%.
Longer follow-up is needed to determine whether the remissions are durable once ibrutinib is stopped – something currently being studied more than a decade after clinicians began using another kinase inhibitor, imatinib (Gleevec), to treat chronic myeloid leukemia, Dr. Byrd said.
He reported 3 grade 3 and no grade 4 infections in treatment-naive patients, and 26 grade 3 infections and 4 grade 4 events in relapsed/refractory patients.
Nearly All Still on Study in Combination Trial
In the second trial, 40 patients received continuous ibrutinib 420 mg daily plus weekly rituximab 365 mg/m2 for 4 weeks, followed by daily ibrutinib plus monthly rituximab until month 6, followed by single-agent ibrutinib. High-risk CLL/SLL was defined as deletion 17p, TP53 mutation, deletion 11q, or less than 3 years remission after first-line chemo-immunotherapy. More than half of patients (58%) had stage IV disease.
After 3-6 months’ follow-up, there were 1 complete response, 32 partial responses, and 3 partial responses with lymphocytosis, Dr. Burger said. In all, 84% of patients experienced more than a 50% reduction in lymph node size.
At the time of the analysis, 95% of all patients and 90% with del 17p continued on therapy without disease progression.
Two patients came off study; one with pneumonia and an intracranial abscess, who died, and another who discontinued due to mucositis/ulcers after four cycles.
Severe toxicities were uncommon in both studies, particularly the considerable immunosuppression and serious infections associated with standard chemo-immunotherapy, the investigators said. The most common event was diarrhea, which was experienced by 54% of patients receiving ibrutinib monotherapy and was largely grade 1 or 2 and resolved after the first couple of cycles, Dr. Byrd said.
Other events included fatigue (29%), upper respiratory infection (29%), rash (28%), nausea (26%) and bone pain (25%). Rates were similar in the combination therapy trial, with bruising also seen in both trials
One of the ongoing phase III trials is the 350-patient RESONATE study evaluating ibrutinib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL or SLL.
Dr. Byrd disclosed research funding from the study sponsor Pharmacyclics, which is developing ibrutinib. Dr. Burger reported consulting for and research funding from Pharmacyclics. Co-authors of both studies are Pharmacyclics employees. Dr. Dearden disclosed no conflicts of interest.
ATLANTA – The experimental oral therapy ibrutinib produces dramatic responses but dodges the significant toxicity seen in conventional treatments for chronic lymphocytic leukemia and small lymphocytic lymphoma.
In one of two phase II trials, the overall response rate was 68% in previously untreated patients and 71% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
The outcome was similar in patients with high-risk relapsed or refractory disease, with the possible exception of those with chromosome 17p deletion. However, with more than half responding, these patients still do better with ibrutinib than with any other therapy explored to date, said Dr. John C. Byrd, director of hematology at Ohio State Comprehensive Cancer Center in Columbus.
"Ibrutinib offers great potential to significantly change the treatment landscape of CLL," he said at a press briefing at the annual meeting of the American Society of Hematology.
In the second trial, combining ibrutinib with the anti-CD20 antibody rituximab (Rituxan) pushed the overall response rate to 83% in high-risk CLL and SLL, said Dr. Jan A. Burger, of the University of Texas M.D. Anderson Cancer Center in Houston.
He noted that several ongoing phase III trials are underway that should accelerate the development of ibrutinib for high-risk patients, who have a high unmet need for alternative treatments.
Ibrutinib is currently not available, even under compassionate use. Despite this, the drug is generating much enthusiasm among clinicians and patients, with some traveling great distances to get into these ongoing trials despite only a 50-50 chance of receiving the drug, said press briefing moderator Dr. Claire Dearden, head of the CLL unit at the Royal Marsden NHS Foundation Trust in London.
"It’s orally active, it’s well tolerated, it’s not chemo, and it produces excellent responses, particularly in patients who are elderly and frail and not necessarily suitable for the more intensive chemotherapy regimens that have become the first-line treatment for the younger, fitter patients," she said.
Ibrutinib, formerly known as PCI-32765, is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK) to enter clinical development. BTK is essential for B-cell receptor signaling, chemokine-mediated migration and adhesion, and toll-like receptor signaling.
96% Survival Estimates at 22 Months
Dr. Byrd reported new and updated results from 31 patients with treatment naive CLL or SLL, 61 with relapsed or refractory disease, and 24 with high-risk relapsed or refractory disease (defined as progression within 24 months of starting a regimen containing at least a nucleoside analogue or bendamustine in combination with a monoclonal antibody or failure to respond to such a regimen).
Patients were given ibrutinib 420 mg or 840 mg daily 2 hours before food until disease progression or intolerable toxicity. Their median age was 72.
After follow-up ranging from 14.7 months to 22.1 months, complete responses occurred in 10% of treatment-naive patients and 2% of relapsed or refractory patients, Dr. Byrd said. Partial responses occurred in 58% and 68%.
At 22 months, progression-free and overall survival estimates were both 96% among previously untreated patients. To put these results in perspective, he said, that with standard cytotoxic chemotherapy, one would expect this number to be 70% or less if patients are young and 50% or less if elderly. "So these are really dramatic results," he added.
In the relapsed or refractory group, progression-free survival was 76% and overall survival 85%.
Longer follow-up is needed to determine whether the remissions are durable once ibrutinib is stopped – something currently being studied more than a decade after clinicians began using another kinase inhibitor, imatinib (Gleevec), to treat chronic myeloid leukemia, Dr. Byrd said.
He reported 3 grade 3 and no grade 4 infections in treatment-naive patients, and 26 grade 3 infections and 4 grade 4 events in relapsed/refractory patients.
Nearly All Still on Study in Combination Trial
In the second trial, 40 patients received continuous ibrutinib 420 mg daily plus weekly rituximab 365 mg/m2 for 4 weeks, followed by daily ibrutinib plus monthly rituximab until month 6, followed by single-agent ibrutinib. High-risk CLL/SLL was defined as deletion 17p, TP53 mutation, deletion 11q, or less than 3 years remission after first-line chemo-immunotherapy. More than half of patients (58%) had stage IV disease.
After 3-6 months’ follow-up, there were 1 complete response, 32 partial responses, and 3 partial responses with lymphocytosis, Dr. Burger said. In all, 84% of patients experienced more than a 50% reduction in lymph node size.
At the time of the analysis, 95% of all patients and 90% with del 17p continued on therapy without disease progression.
Two patients came off study; one with pneumonia and an intracranial abscess, who died, and another who discontinued due to mucositis/ulcers after four cycles.
Severe toxicities were uncommon in both studies, particularly the considerable immunosuppression and serious infections associated with standard chemo-immunotherapy, the investigators said. The most common event was diarrhea, which was experienced by 54% of patients receiving ibrutinib monotherapy and was largely grade 1 or 2 and resolved after the first couple of cycles, Dr. Byrd said.
Other events included fatigue (29%), upper respiratory infection (29%), rash (28%), nausea (26%) and bone pain (25%). Rates were similar in the combination therapy trial, with bruising also seen in both trials
One of the ongoing phase III trials is the 350-patient RESONATE study evaluating ibrutinib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL or SLL.
Dr. Byrd disclosed research funding from the study sponsor Pharmacyclics, which is developing ibrutinib. Dr. Burger reported consulting for and research funding from Pharmacyclics. Co-authors of both studies are Pharmacyclics employees. Dr. Dearden disclosed no conflicts of interest.
AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY
Major Finding: Ibrutinib monotherapy produced an overall response rate of 68% in previously untreated patients and 71% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
Data Source: Phase Ib/II trial of ibrutinib monotherapy and phase II trial of ibrutinib in combination with rituximab.
Disclosures: Dr. Byrd disclosed research funding from the study sponsor Pharmacyclics, which is developing ibrutinib. Dr. Burger reported consulting for and research funding from Pharmacyclics. Coauthors of both studies are Pharmacyclics employees. Dr. Dearden disclosed no conflicts of interest.
Hodgkin's Lymphoma Radiation Linked to Cardiovascular Disease
LOS ANGELES – Hodgkin’s lymphoma survivors who underwent mediastinal radiation therapy for their cancer have a high prevalence of occult cardiovascular disease, a systematic examination of 182 patients showed.
Among 182 asymptomatic, radiation-treated Hodgkin’s lymphoma patients with no prior history of cardiovascular disease, 47 (26%) showed signs of "significant" coronary artery disease (CAD), valvular disease, or left ventricular systolic dysfunction with screening echocardiography done at least 5 years and an average of 15 years after finishing radiation therapy, Dr. Ming Hui Chen reported at the annual scientific sessions of the American Heart Association.
Patients had this high prevalence despite their relatively young age, which ranged from 21 to 65 years and averaged 43 years. Among the subgroup with identified coronary or valvular disease, the average age was 48, ranging from 36 to 65 years, said Dr. Chen, a cardiologist and associate director of the noninvasive cardiac laboratory at Brigham and Women’s Hospital in Boston.
Her analysis also showed that hypertension was the only modifiable risk factor associated with screening-detected CAD and valve disease in these patients. Based on that, "blood pressure modification would likely result in considerable calculated risk reduction for CAD and valve disease in Hodgkin’s lymphoma survivors cured by mediastinal radiation," she concluded.
"The key question is, does radiation directly cause [CAD or valve disease] or does it do so indirectly through hypertension and other cardiac risk factors? Does the hypertension reflect an interaction with arterial stiffness caused by radiation itself?" she asked.
It’s "quite possible" that the hypertension is caused by radiation of "the most distensible part of the arterial system that is mostly responsible for buffering the pulses of the heart," commented Dr. Michael O’Rourke. The problem with this hypothesis is that, if true, "you would expect more systolic than diastolic hypertension," which wasn’t what the data showed, said Dr. O’Rourke, professor of medicine at the University of New South Wales in Sydney.
Dr. Chen and her associates performed screening echocardiography on long-term survivors of Hodgkin’s lymphoma who received mediastinal radiation therapy because results from prior studies had shown that cardiovascular disease is three to five times more prevalent in this population, but despite that, routine screening of these patients for cardiovascular disease is rarely done, she said.
They examined 182 former patients treated for Hodgkin’s lymphoma with mediastinal radiation at any of four Boston-area hospitals during 1967-2006 who were asymptomatic and had no history of cardiovascular disease. All patients underwent transthoracic and stress echocardiographic examinations, and those with findings suggestive of ischemic coronary disease also underwent confirmatory angiography. During cancer treatment the patients had received an average total radiation dose of 3,960 Gy.
Screening identified 24 patients with CAD or valvular disease, and 26 with left ventricular systolic dysfunction (3 of the 47 affected patients had both categories of cardiovascular disease). Some patients had valve disease so advanced that they needed emergency surgery. The most common type of valve disease was aortic stenosis.
Among the people examined, 81% had at least one modifiable cardiac risk factor, including 24 patients with a history of hypertension, and another 24 with a new diagnosis of hypertension. Analysis of all the identified cardiovascular disease risk factors showed that hypertension, an elevated level of high-sensitivity C-reactive protein, and older age were each significantly more prevalent among patients with CAD or valve disease, compared with those without.
But results from a multivariate-adjusted analysis showed that hypertension was the only modifiable risk factor to significantly link with CAD or valve disease. Patients with hypertension were 4.5-fold more likely to have CAD or valve disease, compared with patients without hypertension.
The analysis also showed that for each 5-mm Hg rise in systolic blood pressure, the rate of coronary and valve disease rose by 29%, and for each 5 mm Hg rise in diastolic pressure, the rate of disease rose by 35%, both statistically significant effects, Dr. Chen reported.
Dr. Chen said that she has no disclosures. Dr. O’Rourke is medical director and cofounder of AtCor Medical.
LOS ANGELES – Hodgkin’s lymphoma survivors who underwent mediastinal radiation therapy for their cancer have a high prevalence of occult cardiovascular disease, a systematic examination of 182 patients showed.
Among 182 asymptomatic, radiation-treated Hodgkin’s lymphoma patients with no prior history of cardiovascular disease, 47 (26%) showed signs of "significant" coronary artery disease (CAD), valvular disease, or left ventricular systolic dysfunction with screening echocardiography done at least 5 years and an average of 15 years after finishing radiation therapy, Dr. Ming Hui Chen reported at the annual scientific sessions of the American Heart Association.
Patients had this high prevalence despite their relatively young age, which ranged from 21 to 65 years and averaged 43 years. Among the subgroup with identified coronary or valvular disease, the average age was 48, ranging from 36 to 65 years, said Dr. Chen, a cardiologist and associate director of the noninvasive cardiac laboratory at Brigham and Women’s Hospital in Boston.
Her analysis also showed that hypertension was the only modifiable risk factor associated with screening-detected CAD and valve disease in these patients. Based on that, "blood pressure modification would likely result in considerable calculated risk reduction for CAD and valve disease in Hodgkin’s lymphoma survivors cured by mediastinal radiation," she concluded.
"The key question is, does radiation directly cause [CAD or valve disease] or does it do so indirectly through hypertension and other cardiac risk factors? Does the hypertension reflect an interaction with arterial stiffness caused by radiation itself?" she asked.
It’s "quite possible" that the hypertension is caused by radiation of "the most distensible part of the arterial system that is mostly responsible for buffering the pulses of the heart," commented Dr. Michael O’Rourke. The problem with this hypothesis is that, if true, "you would expect more systolic than diastolic hypertension," which wasn’t what the data showed, said Dr. O’Rourke, professor of medicine at the University of New South Wales in Sydney.
Dr. Chen and her associates performed screening echocardiography on long-term survivors of Hodgkin’s lymphoma who received mediastinal radiation therapy because results from prior studies had shown that cardiovascular disease is three to five times more prevalent in this population, but despite that, routine screening of these patients for cardiovascular disease is rarely done, she said.
They examined 182 former patients treated for Hodgkin’s lymphoma with mediastinal radiation at any of four Boston-area hospitals during 1967-2006 who were asymptomatic and had no history of cardiovascular disease. All patients underwent transthoracic and stress echocardiographic examinations, and those with findings suggestive of ischemic coronary disease also underwent confirmatory angiography. During cancer treatment the patients had received an average total radiation dose of 3,960 Gy.
Screening identified 24 patients with CAD or valvular disease, and 26 with left ventricular systolic dysfunction (3 of the 47 affected patients had both categories of cardiovascular disease). Some patients had valve disease so advanced that they needed emergency surgery. The most common type of valve disease was aortic stenosis.
Among the people examined, 81% had at least one modifiable cardiac risk factor, including 24 patients with a history of hypertension, and another 24 with a new diagnosis of hypertension. Analysis of all the identified cardiovascular disease risk factors showed that hypertension, an elevated level of high-sensitivity C-reactive protein, and older age were each significantly more prevalent among patients with CAD or valve disease, compared with those without.
But results from a multivariate-adjusted analysis showed that hypertension was the only modifiable risk factor to significantly link with CAD or valve disease. Patients with hypertension were 4.5-fold more likely to have CAD or valve disease, compared with patients without hypertension.
The analysis also showed that for each 5-mm Hg rise in systolic blood pressure, the rate of coronary and valve disease rose by 29%, and for each 5 mm Hg rise in diastolic pressure, the rate of disease rose by 35%, both statistically significant effects, Dr. Chen reported.
Dr. Chen said that she has no disclosures. Dr. O’Rourke is medical director and cofounder of AtCor Medical.
LOS ANGELES – Hodgkin’s lymphoma survivors who underwent mediastinal radiation therapy for their cancer have a high prevalence of occult cardiovascular disease, a systematic examination of 182 patients showed.
Among 182 asymptomatic, radiation-treated Hodgkin’s lymphoma patients with no prior history of cardiovascular disease, 47 (26%) showed signs of "significant" coronary artery disease (CAD), valvular disease, or left ventricular systolic dysfunction with screening echocardiography done at least 5 years and an average of 15 years after finishing radiation therapy, Dr. Ming Hui Chen reported at the annual scientific sessions of the American Heart Association.
Patients had this high prevalence despite their relatively young age, which ranged from 21 to 65 years and averaged 43 years. Among the subgroup with identified coronary or valvular disease, the average age was 48, ranging from 36 to 65 years, said Dr. Chen, a cardiologist and associate director of the noninvasive cardiac laboratory at Brigham and Women’s Hospital in Boston.
Her analysis also showed that hypertension was the only modifiable risk factor associated with screening-detected CAD and valve disease in these patients. Based on that, "blood pressure modification would likely result in considerable calculated risk reduction for CAD and valve disease in Hodgkin’s lymphoma survivors cured by mediastinal radiation," she concluded.
"The key question is, does radiation directly cause [CAD or valve disease] or does it do so indirectly through hypertension and other cardiac risk factors? Does the hypertension reflect an interaction with arterial stiffness caused by radiation itself?" she asked.
It’s "quite possible" that the hypertension is caused by radiation of "the most distensible part of the arterial system that is mostly responsible for buffering the pulses of the heart," commented Dr. Michael O’Rourke. The problem with this hypothesis is that, if true, "you would expect more systolic than diastolic hypertension," which wasn’t what the data showed, said Dr. O’Rourke, professor of medicine at the University of New South Wales in Sydney.
Dr. Chen and her associates performed screening echocardiography on long-term survivors of Hodgkin’s lymphoma who received mediastinal radiation therapy because results from prior studies had shown that cardiovascular disease is three to five times more prevalent in this population, but despite that, routine screening of these patients for cardiovascular disease is rarely done, she said.
They examined 182 former patients treated for Hodgkin’s lymphoma with mediastinal radiation at any of four Boston-area hospitals during 1967-2006 who were asymptomatic and had no history of cardiovascular disease. All patients underwent transthoracic and stress echocardiographic examinations, and those with findings suggestive of ischemic coronary disease also underwent confirmatory angiography. During cancer treatment the patients had received an average total radiation dose of 3,960 Gy.
Screening identified 24 patients with CAD or valvular disease, and 26 with left ventricular systolic dysfunction (3 of the 47 affected patients had both categories of cardiovascular disease). Some patients had valve disease so advanced that they needed emergency surgery. The most common type of valve disease was aortic stenosis.
Among the people examined, 81% had at least one modifiable cardiac risk factor, including 24 patients with a history of hypertension, and another 24 with a new diagnosis of hypertension. Analysis of all the identified cardiovascular disease risk factors showed that hypertension, an elevated level of high-sensitivity C-reactive protein, and older age were each significantly more prevalent among patients with CAD or valve disease, compared with those without.
But results from a multivariate-adjusted analysis showed that hypertension was the only modifiable risk factor to significantly link with CAD or valve disease. Patients with hypertension were 4.5-fold more likely to have CAD or valve disease, compared with patients without hypertension.
The analysis also showed that for each 5-mm Hg rise in systolic blood pressure, the rate of coronary and valve disease rose by 29%, and for each 5 mm Hg rise in diastolic pressure, the rate of disease rose by 35%, both statistically significant effects, Dr. Chen reported.
Dr. Chen said that she has no disclosures. Dr. O’Rourke is medical director and cofounder of AtCor Medical.
AT THE ANNUAL SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION
Major Finding: A minimum of 5 years after undergoing radiation therapy for Hodgkin’s lymphoma, 26% of patients had occult cardiovascular disease.
Data Source: Results were taken from a screening echocardiography study of 182 asymptomatic people who received radiation for Hodgkin’s lymphoma in Boston during 1967-2006.
Disclosures: Dr. Chen said that she has no disclosures. Dr. O’Rourke is medical director and cofounder of AtCor Medical.
Anti-TNFs Have Not Raised Lymphoma Risk
WASHINGTON – Anti–tumor necrosis factor therapy does not increase the risk of lymphoma in patients with rheumatoid arthritis.
That’s the conclusion of a study presented in a plenary session here by Dr. Kimme L. Hyrich on Monday, Nov. 12, at the annual meeting of the American College of Rheumatology.
"The challenge in studying whether therapies for rheumatoid arthritis (RA) patients can increase the risk of lymphoma is the knowledge that the disease itself has been associated with this outcome," said Dr. Hyrich.
"It’s possible that with immunosuppression, we may see an increased risk of lymphoma, but equally, if we can control the disease activity that has been associated with this outcome, it’s possible that we actually can see a decrease in lymphoma risk over time."
Dr. Hyrich, of the arthritis research UK epidemiology unit at the University of Manchester (England), and colleagues looked at patients from the British Society for Rheumatology Rheumatoid Arthritis Register (BSRBR-RA), a prospective registry of RA patients taking biologic drugs, recruited between 2001 and 2009.
The treatment group comprised 11,987 patients who started therapy with an anti–tumor necrosis factor (TNF) including infliximab, etanercept, or adalimumab; they were compared to 3,465 patients who were treated solely with nonbiologic disease modifying antirheumatic drugs (DMARDs).
Incident cancers were detected either by flagging in a national cancer database (95% of cancers were identified by this method, according to Dr. Hyrich) in one of six monthly patient and physician questionnaires, or in annual physician questionnaires thereafter.
Subjects were followed until Sept. 30, 2010, or their first lymphoma, or death, whichever came first.
The cutoff date of the study was 2010 because there can be up to a 2-year lag between incident cancer and reporting of those data in the registry, due to rigorous confirmatory processes, said Dr. Hyrich.
The investigators found 84 incident lymphomas over the study period: 20 in the nonbiologic DMARD patients and 64 in the anti-TNF cohort, for a rate of 152 per 100,000 person years versus 96 per 100,000 person-years, respectively.
The tally included five cases of Hodgkin’s lymphomas in the nonbiologic DMARD group and nine in the anti-TNF patients. Among the non-Hodgkin’s lymphoma cases, diffuse large B cell lymphomas accounted for the greatest proportion of cancers.
After adjustment for baseline age, gender, disease activity score, health assessment questionnaire results, disease duration, smoking, and current or previous cyclophosphamide use, the hazard ratio for all lymphomas for anti-TNF users was calculated to be a nonsignificant 1.13 (95% confidence interval, 0.55-2.31).
Similarly, looking at non-Hodgkin’s lymphoma only, Dr. Hyrich determined an adjusted hazard ratio among the anti-TNF patients of 1.26, also nonsignificant (95% CI, 0.58-2.72).
In her presentation, Dr. Hyrich commented that the study was unable to assess risk associated with a particular anti-TNF agent, given that the majority of patients in this real-world cohort had a history of treatment with multiple drugs in the class; indeed, 15% of the cohort had a history of treatment with three or more anti-TNF agents.
"How do you attribute risk in a situation where patients have been exposed to all of these agents?" she said.
"I think further analysis of these cohorts is needed to know whether any exposure to anti-TNFs, or any particular order of anti-TNFs, or any particular duration of anti-TNFs" increases risk.
The researchers stated that they had no disclosures relative to this presentation.
WASHINGTON – Anti–tumor necrosis factor therapy does not increase the risk of lymphoma in patients with rheumatoid arthritis.
That’s the conclusion of a study presented in a plenary session here by Dr. Kimme L. Hyrich on Monday, Nov. 12, at the annual meeting of the American College of Rheumatology.
"The challenge in studying whether therapies for rheumatoid arthritis (RA) patients can increase the risk of lymphoma is the knowledge that the disease itself has been associated with this outcome," said Dr. Hyrich.
"It’s possible that with immunosuppression, we may see an increased risk of lymphoma, but equally, if we can control the disease activity that has been associated with this outcome, it’s possible that we actually can see a decrease in lymphoma risk over time."
Dr. Hyrich, of the arthritis research UK epidemiology unit at the University of Manchester (England), and colleagues looked at patients from the British Society for Rheumatology Rheumatoid Arthritis Register (BSRBR-RA), a prospective registry of RA patients taking biologic drugs, recruited between 2001 and 2009.
The treatment group comprised 11,987 patients who started therapy with an anti–tumor necrosis factor (TNF) including infliximab, etanercept, or adalimumab; they were compared to 3,465 patients who were treated solely with nonbiologic disease modifying antirheumatic drugs (DMARDs).
Incident cancers were detected either by flagging in a national cancer database (95% of cancers were identified by this method, according to Dr. Hyrich) in one of six monthly patient and physician questionnaires, or in annual physician questionnaires thereafter.
Subjects were followed until Sept. 30, 2010, or their first lymphoma, or death, whichever came first.
The cutoff date of the study was 2010 because there can be up to a 2-year lag between incident cancer and reporting of those data in the registry, due to rigorous confirmatory processes, said Dr. Hyrich.
The investigators found 84 incident lymphomas over the study period: 20 in the nonbiologic DMARD patients and 64 in the anti-TNF cohort, for a rate of 152 per 100,000 person years versus 96 per 100,000 person-years, respectively.
The tally included five cases of Hodgkin’s lymphomas in the nonbiologic DMARD group and nine in the anti-TNF patients. Among the non-Hodgkin’s lymphoma cases, diffuse large B cell lymphomas accounted for the greatest proportion of cancers.
After adjustment for baseline age, gender, disease activity score, health assessment questionnaire results, disease duration, smoking, and current or previous cyclophosphamide use, the hazard ratio for all lymphomas for anti-TNF users was calculated to be a nonsignificant 1.13 (95% confidence interval, 0.55-2.31).
Similarly, looking at non-Hodgkin’s lymphoma only, Dr. Hyrich determined an adjusted hazard ratio among the anti-TNF patients of 1.26, also nonsignificant (95% CI, 0.58-2.72).
In her presentation, Dr. Hyrich commented that the study was unable to assess risk associated with a particular anti-TNF agent, given that the majority of patients in this real-world cohort had a history of treatment with multiple drugs in the class; indeed, 15% of the cohort had a history of treatment with three or more anti-TNF agents.
"How do you attribute risk in a situation where patients have been exposed to all of these agents?" she said.
"I think further analysis of these cohorts is needed to know whether any exposure to anti-TNFs, or any particular order of anti-TNFs, or any particular duration of anti-TNFs" increases risk.
The researchers stated that they had no disclosures relative to this presentation.
WASHINGTON – Anti–tumor necrosis factor therapy does not increase the risk of lymphoma in patients with rheumatoid arthritis.
That’s the conclusion of a study presented in a plenary session here by Dr. Kimme L. Hyrich on Monday, Nov. 12, at the annual meeting of the American College of Rheumatology.
"The challenge in studying whether therapies for rheumatoid arthritis (RA) patients can increase the risk of lymphoma is the knowledge that the disease itself has been associated with this outcome," said Dr. Hyrich.
"It’s possible that with immunosuppression, we may see an increased risk of lymphoma, but equally, if we can control the disease activity that has been associated with this outcome, it’s possible that we actually can see a decrease in lymphoma risk over time."
Dr. Hyrich, of the arthritis research UK epidemiology unit at the University of Manchester (England), and colleagues looked at patients from the British Society for Rheumatology Rheumatoid Arthritis Register (BSRBR-RA), a prospective registry of RA patients taking biologic drugs, recruited between 2001 and 2009.
The treatment group comprised 11,987 patients who started therapy with an anti–tumor necrosis factor (TNF) including infliximab, etanercept, or adalimumab; they were compared to 3,465 patients who were treated solely with nonbiologic disease modifying antirheumatic drugs (DMARDs).
Incident cancers were detected either by flagging in a national cancer database (95% of cancers were identified by this method, according to Dr. Hyrich) in one of six monthly patient and physician questionnaires, or in annual physician questionnaires thereafter.
Subjects were followed until Sept. 30, 2010, or their first lymphoma, or death, whichever came first.
The cutoff date of the study was 2010 because there can be up to a 2-year lag between incident cancer and reporting of those data in the registry, due to rigorous confirmatory processes, said Dr. Hyrich.
The investigators found 84 incident lymphomas over the study period: 20 in the nonbiologic DMARD patients and 64 in the anti-TNF cohort, for a rate of 152 per 100,000 person years versus 96 per 100,000 person-years, respectively.
The tally included five cases of Hodgkin’s lymphomas in the nonbiologic DMARD group and nine in the anti-TNF patients. Among the non-Hodgkin’s lymphoma cases, diffuse large B cell lymphomas accounted for the greatest proportion of cancers.
After adjustment for baseline age, gender, disease activity score, health assessment questionnaire results, disease duration, smoking, and current or previous cyclophosphamide use, the hazard ratio for all lymphomas for anti-TNF users was calculated to be a nonsignificant 1.13 (95% confidence interval, 0.55-2.31).
Similarly, looking at non-Hodgkin’s lymphoma only, Dr. Hyrich determined an adjusted hazard ratio among the anti-TNF patients of 1.26, also nonsignificant (95% CI, 0.58-2.72).
In her presentation, Dr. Hyrich commented that the study was unable to assess risk associated with a particular anti-TNF agent, given that the majority of patients in this real-world cohort had a history of treatment with multiple drugs in the class; indeed, 15% of the cohort had a history of treatment with three or more anti-TNF agents.
"How do you attribute risk in a situation where patients have been exposed to all of these agents?" she said.
"I think further analysis of these cohorts is needed to know whether any exposure to anti-TNFs, or any particular order of anti-TNFs, or any particular duration of anti-TNFs" increases risk.
The researchers stated that they had no disclosures relative to this presentation.
AT THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF RHEUMATOLOGY
Major Finding: The incidence of lymphoma in patients with severe RA who were treated with biologic DMARDs was 152 per 100,000 person years versus 96 per 100,000 person years in those treated with nonbiologic DMARDs; however, that difference disappeared after correction for baseline age, gender, DAS score, HAQ, disease duration, use of steroids, current/previous cyclophosphamide use, smoking, and registration date.
Data Source: This finding comes from an analysis of data from the British Society for Rheumatology Rheumatoid Arthritis Register.
Disclosures: The researchers stated that they had no disclosures relative to this presentation.
ASRM: Egg Freezing No Longer 'Experimental'
Oocyte cryopreservation is now an officially sanctioned option for young women whose medical treatments may endanger their fertility.
A report by the American Society for Reproductive Medicine found that advances in egg-freezing techniques now produce rates of pregnancy and healthy babies comparable to those seen with vitro fertilization (IVF) using fresh eggs.
The society went so far as to remove the word "experimental" from the paper, in the hopes that insurance may begin to pay for egg preservation for young women who face gonadotoxic treatments, such as chemotherapy for cancer.
"We are still in the early phases of figuring out the best candidate and the best time of life to elect doing this."
"Egg freezing can be used for patients with medical indications for losing their fertility, such as cancer, impending ovarian failure, or even genetic conditions like Turner syndrome," Dr. Samantha Pfeifer, the paper’s lead author, said during a press briefing. Other indications include a failure to retrieve sufficient sperm on the day of IVF, or the cryopreservation of eggs for couples who can’t, or don’t want to, freeze embryos.
What the paper doesn’t support, however, is using oocyte cryopreservation to delay childbearing, or as any kind of an "insurance policy" for younger women against what might happen to their fertility some time in the future.
"We are aware that this has been marketed vigorously to ensure against future infertility," said Dr. Pfeifer, chair of the ASRM Practice Committee. "Conceptually this seems like a good idea, but there are no data to say that it would help many women. Only 15% of couples will ever seek treatment for infertility, and only a subset of those will attempt IVF, and only a subset of those would need to consider cryopreservation. Only women who were lucky enough to freeze eggs [during their youth], and then become infertile, would be helped by this."
The report examined data from 112 papers on oocyte cryopreservation safety and efficacy. "The largest and most compelling randomized controlled trial compared the use of fresh versus vitrified donor oocytes in 600 recipients," the report noted. "The investigators found that 92.5% of vitrified oocytes survived warming, and that there were no significant differences in fertilization rates (74% vitrified vs. 73% fresh), implantation rates (40% vs. 41%), and pregnancy rates per transfer (55.4% vs. 55.6%) between groups."
The studies’ findings also eased concerns that freezing might compromise egg quality by damaging the meiotic spindle, Dr. Pfeifer said. Advances in the technology of freezing have largely ameliorated that fear.
"Despite concerns regarding spindle abnormalities in cryopreserved oocytes, the incidence of chromosomal abnormalities in human embryos obtained from cryopreserved oocytes is no different from that of control embryos," according to the report. A recent review of more than 900 babies born from frozen eggs found no increased risk of congenital abnormalities, compared with the background population.
However, the paper noted, there are not yet any long-term developmental data on these children.
IVF with frozen oocytes is most successful with women in their 20s and early 30s – as in any other assisted reproduction technique, said coauthor Dr. Eric Widra. This truth touches directly on the issue of elective egg freezing.
"There’s an inherent conflict between the desire to freeze eggs and the need to do it," he said during the briefing. "Young women in their 20s are unlikely to have infertility, and if they do, it’s unlikely to be due to trouble with their eggs, so freezing is an insurance policy many will never need. For the older patient, freezing provides a false sense of security; technically it would be possible, but it may not give them a good chance of a live birth.
"We are still in the early phases of figuring out the best candidate and the best time of life to elect doing this," he said.
Dr. Pfeifer agreed. "We think this application should be used with caution and not be offered indiscriminately to everyone, without counseling about the options. A lot of the women interested in this are in their late 30s and early 40s, and their chance of having a live birth is not as good as younger women. These older patients must be counseled on this. This is not a technology that says, ‘Freeze your eggs so you will have more options down the road.’ The best way to conceive is with your own eggs, through natural intercourse. There are no data that support this as a social mechanism to delay childbearing."
Dr. Pfeifer and Dr. Widra said they had no relevant financial disclosures.
Oocyte cryopreservation is now an officially sanctioned option for young women whose medical treatments may endanger their fertility.
A report by the American Society for Reproductive Medicine found that advances in egg-freezing techniques now produce rates of pregnancy and healthy babies comparable to those seen with vitro fertilization (IVF) using fresh eggs.
The society went so far as to remove the word "experimental" from the paper, in the hopes that insurance may begin to pay for egg preservation for young women who face gonadotoxic treatments, such as chemotherapy for cancer.
"We are still in the early phases of figuring out the best candidate and the best time of life to elect doing this."
"Egg freezing can be used for patients with medical indications for losing their fertility, such as cancer, impending ovarian failure, or even genetic conditions like Turner syndrome," Dr. Samantha Pfeifer, the paper’s lead author, said during a press briefing. Other indications include a failure to retrieve sufficient sperm on the day of IVF, or the cryopreservation of eggs for couples who can’t, or don’t want to, freeze embryos.
What the paper doesn’t support, however, is using oocyte cryopreservation to delay childbearing, or as any kind of an "insurance policy" for younger women against what might happen to their fertility some time in the future.
"We are aware that this has been marketed vigorously to ensure against future infertility," said Dr. Pfeifer, chair of the ASRM Practice Committee. "Conceptually this seems like a good idea, but there are no data to say that it would help many women. Only 15% of couples will ever seek treatment for infertility, and only a subset of those will attempt IVF, and only a subset of those would need to consider cryopreservation. Only women who were lucky enough to freeze eggs [during their youth], and then become infertile, would be helped by this."
The report examined data from 112 papers on oocyte cryopreservation safety and efficacy. "The largest and most compelling randomized controlled trial compared the use of fresh versus vitrified donor oocytes in 600 recipients," the report noted. "The investigators found that 92.5% of vitrified oocytes survived warming, and that there were no significant differences in fertilization rates (74% vitrified vs. 73% fresh), implantation rates (40% vs. 41%), and pregnancy rates per transfer (55.4% vs. 55.6%) between groups."
The studies’ findings also eased concerns that freezing might compromise egg quality by damaging the meiotic spindle, Dr. Pfeifer said. Advances in the technology of freezing have largely ameliorated that fear.
"Despite concerns regarding spindle abnormalities in cryopreserved oocytes, the incidence of chromosomal abnormalities in human embryos obtained from cryopreserved oocytes is no different from that of control embryos," according to the report. A recent review of more than 900 babies born from frozen eggs found no increased risk of congenital abnormalities, compared with the background population.
However, the paper noted, there are not yet any long-term developmental data on these children.
IVF with frozen oocytes is most successful with women in their 20s and early 30s – as in any other assisted reproduction technique, said coauthor Dr. Eric Widra. This truth touches directly on the issue of elective egg freezing.
"There’s an inherent conflict between the desire to freeze eggs and the need to do it," he said during the briefing. "Young women in their 20s are unlikely to have infertility, and if they do, it’s unlikely to be due to trouble with their eggs, so freezing is an insurance policy many will never need. For the older patient, freezing provides a false sense of security; technically it would be possible, but it may not give them a good chance of a live birth.
"We are still in the early phases of figuring out the best candidate and the best time of life to elect doing this," he said.
Dr. Pfeifer agreed. "We think this application should be used with caution and not be offered indiscriminately to everyone, without counseling about the options. A lot of the women interested in this are in their late 30s and early 40s, and their chance of having a live birth is not as good as younger women. These older patients must be counseled on this. This is not a technology that says, ‘Freeze your eggs so you will have more options down the road.’ The best way to conceive is with your own eggs, through natural intercourse. There are no data that support this as a social mechanism to delay childbearing."
Dr. Pfeifer and Dr. Widra said they had no relevant financial disclosures.
Oocyte cryopreservation is now an officially sanctioned option for young women whose medical treatments may endanger their fertility.
A report by the American Society for Reproductive Medicine found that advances in egg-freezing techniques now produce rates of pregnancy and healthy babies comparable to those seen with vitro fertilization (IVF) using fresh eggs.
The society went so far as to remove the word "experimental" from the paper, in the hopes that insurance may begin to pay for egg preservation for young women who face gonadotoxic treatments, such as chemotherapy for cancer.
"We are still in the early phases of figuring out the best candidate and the best time of life to elect doing this."
"Egg freezing can be used for patients with medical indications for losing their fertility, such as cancer, impending ovarian failure, or even genetic conditions like Turner syndrome," Dr. Samantha Pfeifer, the paper’s lead author, said during a press briefing. Other indications include a failure to retrieve sufficient sperm on the day of IVF, or the cryopreservation of eggs for couples who can’t, or don’t want to, freeze embryos.
What the paper doesn’t support, however, is using oocyte cryopreservation to delay childbearing, or as any kind of an "insurance policy" for younger women against what might happen to their fertility some time in the future.
"We are aware that this has been marketed vigorously to ensure against future infertility," said Dr. Pfeifer, chair of the ASRM Practice Committee. "Conceptually this seems like a good idea, but there are no data to say that it would help many women. Only 15% of couples will ever seek treatment for infertility, and only a subset of those will attempt IVF, and only a subset of those would need to consider cryopreservation. Only women who were lucky enough to freeze eggs [during their youth], and then become infertile, would be helped by this."
The report examined data from 112 papers on oocyte cryopreservation safety and efficacy. "The largest and most compelling randomized controlled trial compared the use of fresh versus vitrified donor oocytes in 600 recipients," the report noted. "The investigators found that 92.5% of vitrified oocytes survived warming, and that there were no significant differences in fertilization rates (74% vitrified vs. 73% fresh), implantation rates (40% vs. 41%), and pregnancy rates per transfer (55.4% vs. 55.6%) between groups."
The studies’ findings also eased concerns that freezing might compromise egg quality by damaging the meiotic spindle, Dr. Pfeifer said. Advances in the technology of freezing have largely ameliorated that fear.
"Despite concerns regarding spindle abnormalities in cryopreserved oocytes, the incidence of chromosomal abnormalities in human embryos obtained from cryopreserved oocytes is no different from that of control embryos," according to the report. A recent review of more than 900 babies born from frozen eggs found no increased risk of congenital abnormalities, compared with the background population.
However, the paper noted, there are not yet any long-term developmental data on these children.
IVF with frozen oocytes is most successful with women in their 20s and early 30s – as in any other assisted reproduction technique, said coauthor Dr. Eric Widra. This truth touches directly on the issue of elective egg freezing.
"There’s an inherent conflict between the desire to freeze eggs and the need to do it," he said during the briefing. "Young women in their 20s are unlikely to have infertility, and if they do, it’s unlikely to be due to trouble with their eggs, so freezing is an insurance policy many will never need. For the older patient, freezing provides a false sense of security; technically it would be possible, but it may not give them a good chance of a live birth.
"We are still in the early phases of figuring out the best candidate and the best time of life to elect doing this," he said.
Dr. Pfeifer agreed. "We think this application should be used with caution and not be offered indiscriminately to everyone, without counseling about the options. A lot of the women interested in this are in their late 30s and early 40s, and their chance of having a live birth is not as good as younger women. These older patients must be counseled on this. This is not a technology that says, ‘Freeze your eggs so you will have more options down the road.’ The best way to conceive is with your own eggs, through natural intercourse. There are no data that support this as a social mechanism to delay childbearing."
Dr. Pfeifer and Dr. Widra said they had no relevant financial disclosures.
Community Oncology Podcast - Carfilzomib and multiple myeloma
What’s the role of parenteral iron use in the oncology clinic? How does carfilzomib fit into the treatment of multiple myeloma? Listen to the the September podcast of Community Oncology from Editor-in-Chief Dr. David H. Henry.
What’s the role of parenteral iron use in the oncology clinic? How does carfilzomib fit into the treatment of multiple myeloma? Listen to the the September podcast of Community Oncology from Editor-in-Chief Dr. David H. Henry.
What’s the role of parenteral iron use in the oncology clinic? How does carfilzomib fit into the treatment of multiple myeloma? Listen to the the September podcast of Community Oncology from Editor-in-Chief Dr. David H. Henry.
Long-Term Follow-Up Warranted After Gastric MALT Lymphoma Remission
As many as 80% of gastric MALT lymphoma patients achieve remission after Helicobacter pylori eradication, yet these patients remain at a significantly increased risk for second gastric cancers and lymphomas, reported Dr. Thomas Wündisch and his colleagues in Gastroenterology.
"The clinical consequence of this should be yearly lifelong endoscopic follow-up in all patients with a history of GML [gastric MALT lymphoma] to detect gastric cancer as early as possible," they wrote.
Dr. Wündisch, of Heinrich-Heine-Universität in Düsseldorf, Germany, and his colleagues studied 120 patients (63 female, mean age 62 years) recruited between June 1993 and July 1999 with stage EI1 gastric mucosa–associated lymphoid tissue (MALT) lymphoma according to the Ann Arbor system, where lymphoma is limited to the mucosa and submucosa of the stomach with no lymph node involvement.
Patients in this multicenter study underwent H. pylori eradication therapy consisting of a 2-week course of amoxicillin (750 mg three times daily) and omeprazole (40 mg three times daily).
Endoscopy was performed monthly until complete histologic remission, defined as macroscopic disappearance of lymphoma and absence of lymphoma on biopsy in two consecutive analyses, and then every 6-12 months. Patients were followed for a median of 122 months after H. pylori eradication (range, 1-171 months).
Dr. Wündisch and his colleagues reported that 96 of the 120 patients with complete follow-up (80%) achieved complete GML remission between 1 and 28 months after eradication therapy began, and 80% of them (77/96) remained disease free (Gastroenterology 2012 [doi: 10.1053/j.gastro.2012.06.035]).
Histologic residual disease was seen in 16 out of 96 patients; indeed, it was likely "ongoing histological residual disease rather than complete remission, as the microscopic lesions were small and often found only upon examination of serial sections of one of multiple biopsies."
A "watch and wait" approach was used in these cases, and all but one patient showed complete remission again at the last time point, with a median second remission duration of 46 months. There was also no progression.
"We strongly support this strategy," the investigators wrote.
Overall, the 96 patients with complete GML remission had a 5-year survival rate of 94%, and a 10-year survival of 87%.
Nevertheless, the researchers observed a morbidity ratio of 8.567 for gastric cancer among these patients (95% confidence interval, 3.566-20.582; P less than .001) and 18.621 for non-Hodgkin’s lymphoma (95% CI, 8.365-41.448; P less than 10–6), compared with the general population. The morbidity rate for all cancers was also elevated, at 1.689, but this was not statistically significant.
According to the researchers, although treatment-related factors often contribute to the development of second cancers in patients with lymphoma, the 2-week-long H. pylori regimen employed was unlikely to cause long-term toxic effects.
"Patient-related factors, such as gene polymorphisms, might play a more important role in the development of GML and second cancers in our patients, but these factors have yet to be identified," they said.
In any case, "currently, follow-up of patients without significant comorbidities should extend beyond 5 years for detecting reinfection, relapse, second lymphoma, and early gastric cancer."
The authors stated that the study was funded by a grant from Deutsche Krebshilfe, and they had no personal disclosures.
As many as 80% of gastric MALT lymphoma patients achieve remission after Helicobacter pylori eradication, yet these patients remain at a significantly increased risk for second gastric cancers and lymphomas, reported Dr. Thomas Wündisch and his colleagues in Gastroenterology.
"The clinical consequence of this should be yearly lifelong endoscopic follow-up in all patients with a history of GML [gastric MALT lymphoma] to detect gastric cancer as early as possible," they wrote.
Dr. Wündisch, of Heinrich-Heine-Universität in Düsseldorf, Germany, and his colleagues studied 120 patients (63 female, mean age 62 years) recruited between June 1993 and July 1999 with stage EI1 gastric mucosa–associated lymphoid tissue (MALT) lymphoma according to the Ann Arbor system, where lymphoma is limited to the mucosa and submucosa of the stomach with no lymph node involvement.
Patients in this multicenter study underwent H. pylori eradication therapy consisting of a 2-week course of amoxicillin (750 mg three times daily) and omeprazole (40 mg three times daily).
Endoscopy was performed monthly until complete histologic remission, defined as macroscopic disappearance of lymphoma and absence of lymphoma on biopsy in two consecutive analyses, and then every 6-12 months. Patients were followed for a median of 122 months after H. pylori eradication (range, 1-171 months).
Dr. Wündisch and his colleagues reported that 96 of the 120 patients with complete follow-up (80%) achieved complete GML remission between 1 and 28 months after eradication therapy began, and 80% of them (77/96) remained disease free (Gastroenterology 2012 [doi: 10.1053/j.gastro.2012.06.035]).
Histologic residual disease was seen in 16 out of 96 patients; indeed, it was likely "ongoing histological residual disease rather than complete remission, as the microscopic lesions were small and often found only upon examination of serial sections of one of multiple biopsies."
A "watch and wait" approach was used in these cases, and all but one patient showed complete remission again at the last time point, with a median second remission duration of 46 months. There was also no progression.
"We strongly support this strategy," the investigators wrote.
Overall, the 96 patients with complete GML remission had a 5-year survival rate of 94%, and a 10-year survival of 87%.
Nevertheless, the researchers observed a morbidity ratio of 8.567 for gastric cancer among these patients (95% confidence interval, 3.566-20.582; P less than .001) and 18.621 for non-Hodgkin’s lymphoma (95% CI, 8.365-41.448; P less than 10–6), compared with the general population. The morbidity rate for all cancers was also elevated, at 1.689, but this was not statistically significant.
According to the researchers, although treatment-related factors often contribute to the development of second cancers in patients with lymphoma, the 2-week-long H. pylori regimen employed was unlikely to cause long-term toxic effects.
"Patient-related factors, such as gene polymorphisms, might play a more important role in the development of GML and second cancers in our patients, but these factors have yet to be identified," they said.
In any case, "currently, follow-up of patients without significant comorbidities should extend beyond 5 years for detecting reinfection, relapse, second lymphoma, and early gastric cancer."
The authors stated that the study was funded by a grant from Deutsche Krebshilfe, and they had no personal disclosures.
As many as 80% of gastric MALT lymphoma patients achieve remission after Helicobacter pylori eradication, yet these patients remain at a significantly increased risk for second gastric cancers and lymphomas, reported Dr. Thomas Wündisch and his colleagues in Gastroenterology.
"The clinical consequence of this should be yearly lifelong endoscopic follow-up in all patients with a history of GML [gastric MALT lymphoma] to detect gastric cancer as early as possible," they wrote.
Dr. Wündisch, of Heinrich-Heine-Universität in Düsseldorf, Germany, and his colleagues studied 120 patients (63 female, mean age 62 years) recruited between June 1993 and July 1999 with stage EI1 gastric mucosa–associated lymphoid tissue (MALT) lymphoma according to the Ann Arbor system, where lymphoma is limited to the mucosa and submucosa of the stomach with no lymph node involvement.
Patients in this multicenter study underwent H. pylori eradication therapy consisting of a 2-week course of amoxicillin (750 mg three times daily) and omeprazole (40 mg three times daily).
Endoscopy was performed monthly until complete histologic remission, defined as macroscopic disappearance of lymphoma and absence of lymphoma on biopsy in two consecutive analyses, and then every 6-12 months. Patients were followed for a median of 122 months after H. pylori eradication (range, 1-171 months).
Dr. Wündisch and his colleagues reported that 96 of the 120 patients with complete follow-up (80%) achieved complete GML remission between 1 and 28 months after eradication therapy began, and 80% of them (77/96) remained disease free (Gastroenterology 2012 [doi: 10.1053/j.gastro.2012.06.035]).
Histologic residual disease was seen in 16 out of 96 patients; indeed, it was likely "ongoing histological residual disease rather than complete remission, as the microscopic lesions were small and often found only upon examination of serial sections of one of multiple biopsies."
A "watch and wait" approach was used in these cases, and all but one patient showed complete remission again at the last time point, with a median second remission duration of 46 months. There was also no progression.
"We strongly support this strategy," the investigators wrote.
Overall, the 96 patients with complete GML remission had a 5-year survival rate of 94%, and a 10-year survival of 87%.
Nevertheless, the researchers observed a morbidity ratio of 8.567 for gastric cancer among these patients (95% confidence interval, 3.566-20.582; P less than .001) and 18.621 for non-Hodgkin’s lymphoma (95% CI, 8.365-41.448; P less than 10–6), compared with the general population. The morbidity rate for all cancers was also elevated, at 1.689, but this was not statistically significant.
According to the researchers, although treatment-related factors often contribute to the development of second cancers in patients with lymphoma, the 2-week-long H. pylori regimen employed was unlikely to cause long-term toxic effects.
"Patient-related factors, such as gene polymorphisms, might play a more important role in the development of GML and second cancers in our patients, but these factors have yet to be identified," they said.
In any case, "currently, follow-up of patients without significant comorbidities should extend beyond 5 years for detecting reinfection, relapse, second lymphoma, and early gastric cancer."
The authors stated that the study was funded by a grant from Deutsche Krebshilfe, and they had no personal disclosures.
FROM GASTROENTEROLOGY
Major Finding: Of 120 participants, 96 (80%) achieved complete remission of gastric MALT lymphoma, and 80% of them (77/96) remained disease free.
Data Source: A prospective, multicenter trial of 120 patients over a median 10 years of follow-up.
Disclosures: The authors stated that the study was funded by a grant from Deutsche Krebshilfe, and they had no personal disclosures.
Carfilzomib and bortezomib therapy in patients with multiple myeloma
In July 2012, carfilzomib was given accelerated approval by the Food and Drug Administration for the treatment of patients with multiple myeloma (MM) who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have exhibited disease progression during or within 60 days of completing their last therapy. The approval was based on results of a single-arm, multicenter phase 2 trial of carfilzomib in patients with relapsed and refractory MM. As a condition of the accelerated approval, the manufacturer of the drug has to submit a final analysis of an ongoing phase 3 trial that compares carfilzomib plus lenalidomide plus low-dose dexamethasone with lenalidomide plus low-dose dexamethasone in patients with relapsed and refractory MM after 1 to 3 previous therapies. The primary end point of this trial is progression-free survival (PFS)...
*For a PDF of the full article and accompanying Commentaries, click on the links to the left of this introduction.
In July 2012, carfilzomib was given accelerated approval by the Food and Drug Administration for the treatment of patients with multiple myeloma (MM) who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have exhibited disease progression during or within 60 days of completing their last therapy. The approval was based on results of a single-arm, multicenter phase 2 trial of carfilzomib in patients with relapsed and refractory MM. As a condition of the accelerated approval, the manufacturer of the drug has to submit a final analysis of an ongoing phase 3 trial that compares carfilzomib plus lenalidomide plus low-dose dexamethasone with lenalidomide plus low-dose dexamethasone in patients with relapsed and refractory MM after 1 to 3 previous therapies. The primary end point of this trial is progression-free survival (PFS)...
*For a PDF of the full article and accompanying Commentaries, click on the links to the left of this introduction.
In July 2012, carfilzomib was given accelerated approval by the Food and Drug Administration for the treatment of patients with multiple myeloma (MM) who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have exhibited disease progression during or within 60 days of completing their last therapy. The approval was based on results of a single-arm, multicenter phase 2 trial of carfilzomib in patients with relapsed and refractory MM. As a condition of the accelerated approval, the manufacturer of the drug has to submit a final analysis of an ongoing phase 3 trial that compares carfilzomib plus lenalidomide plus low-dose dexamethasone with lenalidomide plus low-dose dexamethasone in patients with relapsed and refractory MM after 1 to 3 previous therapies. The primary end point of this trial is progression-free survival (PFS)...
*For a PDF of the full article and accompanying Commentaries, click on the links to the left of this introduction.