Transthoracic two-dimensional echocardiography appears to be inadequate for identifying cardiomyopathy in adults who survive childhood cancer, according to a cross-sectional study published online July 16 in the Journal of Clinical Oncology.

Compared with cardiac magnetic resonance imaging (CMRI), which is considered the reference standard to which other cardiac imaging techniques are compared, 2-D echocardiography had a sensitivity of only 25% and a false-negative rate of 75% in identifying cardiomyopathy in a study of 134 adult survivors of childhood cancer, said Dr. Gregory T. Armstrong of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital, Memphis, and his associates.

In these relatively young and apparently healthy study subjects who had never been diagnosed as having any cardiac abnormality, nearly half (48%) were found to have the reduced cardiac mass indicative of cancer therapy–related injury. And fully 11% of subjects who were judged to have a normal ejection fraction (EF) on 2-D echocardiography were actually proved to have an EF of less than 50% on CMRI, the researchers noted.

That number easily could have been higher, but there happened to be a low absolute number of patients (16) with this degree of EF impairment in the small cohort, they pointed out.

Adults who survive childhood cancer are at risk for cardiomyopathy because of their exposure to chemotherapy and radiotherapy. Current guidelines recommend screening such adults by transthoracic 2-D echocardiography because it is noninvasive, widely available, and less expensive than other techniques.

However, the quality of the acoustic windows obtained on 2-D echo varies widely, and the method depends on geometric assumptions that may not be valid in patients who have dilated or remodeled ventricles. Three-dimensional echocardiography yields somewhat more accurate results but is not as widely available. CMRI is the most accurate noninvasive imaging technique, but is more expensive and is even less widely available, Dr. Armstrong and his colleagues explained.

They assessed the accuracy of 2-D and 3-D echocardiography against CMRI as a screen for cardiomyopathy in a longitudinal cohort of 134 adults who had been treated at St. Jude’s for childhood cancer 18-38 years earlier. All had received chest-directed radiotherapy and/or anthracycline chemotherapy, both of which are known to impair cardiac function during treatment and to raise the risk of reduced left ventricular function later in life.

The most common pediatric malignancies were acute lymphoblastic leukemia (44 subjects) and Hodgkin’s lymphoma (37 subjects).

The median age at echocardiographic screening in adulthood was 39 years (range, 22-53 years).

Of the study subjects, 20 were unable to complete CMRI for a variety of reasons. Future studies that compare imaging techniques should take into consideration this relatively high noncompletion rate (15%) for CMRI, especially in cost-benefit analyses, Dr. Armstrong and his colleagues said (J. Clin. Oncol. 2012 July 16 [doi:10.1200/JCO.2011.40.3584]).

In the remaining 114 subjects, 2-D echocardiography consistently overestimated left ventricular ejection fraction (LVEF) and underestimated both end-systolic and end-diastolic ventricular volumes.

In all, 16 subjects were identified as having markedly decreased LVEF (50% or more) by CMRI, but only 4 of them were so identified by 2-D echocardiography and only 11 of them by 3-D echocardiography.

Compared with CMRI, the sensitivity of 2-D echocardiography was only 25%; that of 3-D echo was better but still inadequate, at only 53%. And false-negative rates were high with both 2-D echocardiography (75%) and 3-D echocardiography (47%).

Of particular concern was the finding that on CMRI, 32% of the study subjects had an LVEF that was well below normal. The rate in the subgroup of patients who had received both chest irradiation and anthracycline during childhood cancer treatment was even higher, at 42%.

A total of 48% of the study subjects had a cardiac mass that was at least 2 standard deviations below normal for their age and sex, a clear sign of cardiotoxicity from their childhood cancer treatment. "Notably, even patients who received less than 150 mg/m² of anthracyclines had a high prevalence of reduced EF (27%), stroke volume (29%), or cardiac mass (56%)," the investigators said.

Estimates derived from Medicare data suggest that at roughly $449 each, CMRI examinations cost about $217 more than does echocardiography ($232 each). Given the high rate of cardiomyopathy discovered in this cohort, and the poor sensitivity of echocardiography as a screening tool, this cost difference may be small enough to warrant a switch in the current screening recommendations from echocardiography to CMRI.

The additional cost of a CMRI-only screening strategy per case of cardiotoxicity correctly identified would be only $1,973, they noted.

The study findings suggest that in this high-risk patient population that was exposed to cardiotoxic therapy during childhood, "consideration should be given to referring survivors with an EF of 50%-59% on [2-D echocardiography] for comprehensive cardiology assessment that includes cardiac history, symptom index, and examination; biomarker assessment; consideration of [CMRI]; functional assessment by treadmill testing; and possibly medical therapy to prevent progression of disease," Dr. Armstrong and his associates said.

This study was supported by the American Society of Clinical Oncology and the American Lebanese-Syrian Associated Charities. Dr. Armstrong’s associates reported ties to General Electric and Philips Healthcare.

Transthoracic two-dimensional echocardiography appears to be inadequate for identifying cardiomyopathy in adults who survive childhood cancer, according to a cross-sectional study published online July 16 in the Journal of Clinical Oncology.

Compared with cardiac magnetic resonance imaging (CMRI), which is considered the reference standard to which other cardiac imaging techniques are compared, 2-D echocardiography had a sensitivity of only 25% and a false-negative rate of 75% in identifying cardiomyopathy in a study of 134 adult survivors of childhood cancer, said Dr. Gregory T. Armstrong of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital, Memphis, and his associates.

In these relatively young and apparently healthy study subjects who had never been diagnosed as having any cardiac abnormality, nearly half (48%) were found to have the reduced cardiac mass indicative of cancer therapy–related injury. And fully 11% of subjects who were judged to have a normal ejection fraction (EF) on 2-D echocardiography were actually proved to have an EF of less than 50% on CMRI, the researchers noted.

That number easily could have been higher, but there happened to be a low absolute number of patients (16) with this degree of EF impairment in the small cohort, they pointed out.

Adults who survive childhood cancer are at risk for cardiomyopathy because of their exposure to chemotherapy and radiotherapy. Current guidelines recommend screening such adults by transthoracic 2-D echocardiography because it is noninvasive, widely available, and less expensive than other techniques.

However, the quality of the acoustic windows obtained on 2-D echo varies widely, and the method depends on geometric assumptions that may not be valid in patients who have dilated or remodeled ventricles. Three-dimensional echocardiography yields somewhat more accurate results but is not as widely available. CMRI is the most accurate noninvasive imaging technique, but is more expensive and is even less widely available, Dr. Armstrong and his colleagues explained.

They assessed the accuracy of 2-D and 3-D echocardiography against CMRI as a screen for cardiomyopathy in a longitudinal cohort of 134 adults who had been treated at St. Jude’s for childhood cancer 18-38 years earlier. All had received chest-directed radiotherapy and/or anthracycline chemotherapy, both of which are known to impair cardiac function during treatment and to raise the risk of reduced left ventricular function later in life.

The most common pediatric malignancies were acute lymphoblastic leukemia (44 subjects) and Hodgkin’s lymphoma (37 subjects).

The median age at echocardiographic screening in adulthood was 39 years (range, 22-53 years).

Of the study subjects, 20 were unable to complete CMRI for a variety of reasons. Future studies that compare imaging techniques should take into consideration this relatively high noncompletion rate (15%) for CMRI, especially in cost-benefit analyses, Dr. Armstrong and his colleagues said (J. Clin. Oncol. 2012 July 16 [doi:10.1200/JCO.2011.40.3584]).

In the remaining 114 subjects, 2-D echocardiography consistently overestimated left ventricular ejection fraction (LVEF) and underestimated both end-systolic and end-diastolic ventricular volumes.

In all, 16 subjects were identified as having markedly decreased LVEF (50% or more) by CMRI, but only 4 of them were so identified by 2-D echocardiography and only 11 of them by 3-D echocardiography.

Compared with CMRI, the sensitivity of 2-D echocardiography was only 25%; that of 3-D echo was better but still inadequate, at only 53%. And false-negative rates were high with both 2-D echocardiography (75%) and 3-D echocardiography (47%).

Of particular concern was the finding that on CMRI, 32% of the study subjects had an LVEF that was well below normal. The rate in the subgroup of patients who had received both chest irradiation and anthracycline during childhood cancer treatment was even higher, at 42%.

A total of 48% of the study subjects had a cardiac mass that was at least 2 standard deviations below normal for their age and sex, a clear sign of cardiotoxicity from their childhood cancer treatment. "Notably, even patients who received less than 150 mg/m² of anthracyclines had a high prevalence of reduced EF (27%), stroke volume (29%), or cardiac mass (56%)," the investigators said.

Estimates derived from Medicare data suggest that at roughly $449 each, CMRI examinations cost about $217 more than does echocardiography ($232 each). Given the high rate of cardiomyopathy discovered in this cohort, and the poor sensitivity of echocardiography as a screening tool, this cost difference may be small enough to warrant a switch in the current screening recommendations from echocardiography to CMRI.

The additional cost of a CMRI-only screening strategy per case of cardiotoxicity correctly identified would be only $1,973, they noted.

The study findings suggest that in this high-risk patient population that was exposed to cardiotoxic therapy during childhood, "consideration should be given to referring survivors with an EF of 50%-59% on [2-D echocardiography] for comprehensive cardiology assessment that includes cardiac history, symptom index, and examination; biomarker assessment; consideration of [CMRI]; functional assessment by treadmill testing; and possibly medical therapy to prevent progression of disease," Dr. Armstrong and his associates said.

This study was supported by the American Society of Clinical Oncology and the American Lebanese-Syrian Associated Charities. Dr. Armstrong’s associates reported ties to General Electric and Philips Healthcare.

Transthoracic two-dimensional echocardiography appears to be inadequate for identifying cardiomyopathy in adults who survive childhood cancer, according to a cross-sectional study published online July 16 in the Journal of Clinical Oncology.

Compared with cardiac magnetic resonance imaging (CMRI), which is considered the reference standard to which other cardiac imaging techniques are compared, 2-D echocardiography had a sensitivity of only 25% and a false-negative rate of 75% in identifying cardiomyopathy in a study of 134 adult survivors of childhood cancer, said Dr. Gregory T. Armstrong of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital, Memphis, and his associates.

In these relatively young and apparently healthy study subjects who had never been diagnosed as having any cardiac abnormality, nearly half (48%) were found to have the reduced cardiac mass indicative of cancer therapy–related injury. And fully 11% of subjects who were judged to have a normal ejection fraction (EF) on 2-D echocardiography were actually proved to have an EF of less than 50% on CMRI, the researchers noted.

That number easily could have been higher, but there happened to be a low absolute number of patients (16) with this degree of EF impairment in the small cohort, they pointed out.

Adults who survive childhood cancer are at risk for cardiomyopathy because of their exposure to chemotherapy and radiotherapy. Current guidelines recommend screening such adults by transthoracic 2-D echocardiography because it is noninvasive, widely available, and less expensive than other techniques.

However, the quality of the acoustic windows obtained on 2-D echo varies widely, and the method depends on geometric assumptions that may not be valid in patients who have dilated or remodeled ventricles. Three-dimensional echocardiography yields somewhat more accurate results but is not as widely available. CMRI is the most accurate noninvasive imaging technique, but is more expensive and is even less widely available, Dr. Armstrong and his colleagues explained.

They assessed the accuracy of 2-D and 3-D echocardiography against CMRI as a screen for cardiomyopathy in a longitudinal cohort of 134 adults who had been treated at St. Jude’s for childhood cancer 18-38 years earlier. All had received chest-directed radiotherapy and/or anthracycline chemotherapy, both of which are known to impair cardiac function during treatment and to raise the risk of reduced left ventricular function later in life.

The most common pediatric malignancies were acute lymphoblastic leukemia (44 subjects) and Hodgkin’s lymphoma (37 subjects).

The median age at echocardiographic screening in adulthood was 39 years (range, 22-53 years).

Of the study subjects, 20 were unable to complete CMRI for a variety of reasons. Future studies that compare imaging techniques should take into consideration this relatively high noncompletion rate (15%) for CMRI, especially in cost-benefit analyses, Dr. Armstrong and his colleagues said (J. Clin. Oncol. 2012 July 16 [doi:10.1200/JCO.2011.40.3584]).

In the remaining 114 subjects, 2-D echocardiography consistently overestimated left ventricular ejection fraction (LVEF) and underestimated both end-systolic and end-diastolic ventricular volumes.

In all, 16 subjects were identified as having markedly decreased LVEF (50% or more) by CMRI, but only 4 of them were so identified by 2-D echocardiography and only 11 of them by 3-D echocardiography.

Compared with CMRI, the sensitivity of 2-D echocardiography was only 25%; that of 3-D echo was better but still inadequate, at only 53%. And false-negative rates were high with both 2-D echocardiography (75%) and 3-D echocardiography (47%).

Of particular concern was the finding that on CMRI, 32% of the study subjects had an LVEF that was well below normal. The rate in the subgroup of patients who had received both chest irradiation and anthracycline during childhood cancer treatment was even higher, at 42%.

A total of 48% of the study subjects had a cardiac mass that was at least 2 standard deviations below normal for their age and sex, a clear sign of cardiotoxicity from their childhood cancer treatment. "Notably, even patients who received less than 150 mg/m² of anthracyclines had a high prevalence of reduced EF (27%), stroke volume (29%), or cardiac mass (56%)," the investigators said.

Estimates derived from Medicare data suggest that at roughly $449 each, CMRI examinations cost about $217 more than does echocardiography ($232 each). Given the high rate of cardiomyopathy discovered in this cohort, and the poor sensitivity of echocardiography as a screening tool, this cost difference may be small enough to warrant a switch in the current screening recommendations from echocardiography to CMRI.

The additional cost of a CMRI-only screening strategy per case of cardiotoxicity correctly identified would be only $1,973, they noted.

The study findings suggest that in this high-risk patient population that was exposed to cardiotoxic therapy during childhood, "consideration should be given to referring survivors with an EF of 50%-59% on [2-D echocardiography] for comprehensive cardiology assessment that includes cardiac history, symptom index, and examination; biomarker assessment; consideration of [CMRI]; functional assessment by treadmill testing; and possibly medical therapy to prevent progression of disease," Dr. Armstrong and his associates said.

This study was supported by the American Society of Clinical Oncology and the American Lebanese-Syrian Associated Charities. Dr. Armstrong’s associates reported ties to General Electric and Philips Healthcare.

Maraviroc, an ingredient in retroviral cocktails used to treat HIV, might also have a role in preventing acute graft-vs.-host disease after allogeneic hematopoietic stem-cell transplantation.

Adding a 1-month course of maraviroc (Selzentry), an inhibitor of T-cell chemotaxis, to standard prophylaxis appeared to reduce the incidence of acute graft-vs.-host disease (GVHD) after allogeneic transplants in a single-center study of 38 adults with hematologic cancers, which was published online July 11 in the New England Journal of Medicine.

At the same time, maraviroc did not disrupt hematopoietic engraftment, raise the incidence of cancer recurrence, or increase infectious complications, said Dr. Ran Reshef of the Abramson Cancer Center and the division of hematology and oncology at the University of Pennsylvania, Philadelphia, and his associates.

Maraviroc is the first drug available in the class of chemokine (C-C motif) receptor 5 (CCR5) antagonists. It prevents the signaling of CCR5 and its ligands, "which have been implicated in the pathogenesis of GVHD and solid-organ rejection." CCR5 is crucial to lymphocyte recruitment to tissues involved in GVHD. Blockade of CCR5 protects against GVHD in mouse models, and human genetic studies have shown that certain polymorphisms in the gene that encodes CCR5 are protective against GVHD.

Currently, maraviroc is used in combination antiretroviral therapy for a subtype of HIV that uses only the CCR5 coreceptor to enter cells. "We hypothesized that CCR5 blockade with maraviroc early after allogeneic hematopoietic stem-cell transplantation might inhibit lymphocyte trafficking and decrease the incidence of acute GVHD," Dr. Reshef and his colleagues said (N. Engl. J. Med. 2012;367:135-45).

They conducted a phase I clinical trial to confirm that the established dose for HIV patients was safe, and achieved target drug levels in patients who have undergone reduced-intensity conditioning and stem-cell transplantation. The cohort included patients with acute myeloid leukemia, non-Hodgkin’s lymphoma, myelodysplastic syndromes, myeloproliferative disorder, chronic lymphocytic leukemia, aplastic anemia, multiple myeloma, Hodgkin’s lymphoma, and chronic myeloid leukemia.

All the study subjects received standard GVHD prophylaxis including oral tacrolimus and IV methotrexate, as well as standard antimicrobial prophylaxis with voriconazole, acyclovir, and trimethoprim-sulfamethoxazole.

Most of the study subjects were considered high risk for GVHD because of their age (68% were older than 60 years), donor-recipient HLA incompatibility, cancer severity, and heavy burden of comorbidity. "The anticipated incidence of acute GVHD in similar patients is typically more than 50%," the investigators noted.

After the dose-confirming study, the researchers then performed a phase II clinical trial evaluating 35 of the same patients. Maraviroc (300 mg) was given orally twice daily from 2 days before transplantation until day 30. The study subjects were followed for a median of 20 months (range, 14-35 months).

Engraftment was rapid, and maraviroc produced few toxic effects. "Administration of the drug was briefly suspended in 7 patients because of grade 3 abnormalities on liver-function testing (in 2 patients) or grade 3 or 4 mucositis (in 5). Liver-function abnormalities did not recur when the drug was restarted," Dr. Reshef and his associates said.

The primary end point – the cumulative incidence of GVHD at day 100 – was 14.7% for grade II-IV acute disease. Remarkably, there were no cases of GVHD involving the liver or gut.

Similarly, at 6 months GVHD remained largely confined to the skin, and involved the liver in only 2.9% of cases and the gut in only 8.8%. At this point the incidence of moderate disease was 23.6% and severe disease only 5.9%. In comparison, these rates at their institution typically are 38.5% and 21.9%, the researchers said.

In the subset of 11 patients who received stem cells from an HLA-matched sibling, there were no cases of acute GVHD at day 100 and no moderate to severe GVHD at 6 months.

Thus, cases of skin GVHD developed at the expected rates, but the absence of liver or gut GVHD lead to a low incidence of severe disease.

"The outcomes of this study are especially favorable considering the study population, which included older patients and a high proportion of matched unrelated donors and HLA-mismatched donors." In addition, almost half the study subjects had major coexisting illnesses.

Cumulative rates of relapse and death were not higher than expected for patients with these disease characteristics who were given reduced-intensity regimens, the authors said.

Because this was a single-center, phase-I/phase-II trial involving only 38 patients, "the value of maraviroc in lowering the rate of acute GVHD will need to be assessed in a prospective, randomized trial," Dr. Reshef and his colleagues added.

This study was supported by Pfizer, maker of maraviroc; the Leukemia and Lymphoma Society; the National Institutes of Health; the Abramson Cancer Center; the American Society of Hematology; and the American Society of Clinical Oncology. Dr. Reshef’s associates reported ties to Pfizer, Bristol-Myers Squibb, Celgene, and Millennium.

Maraviroc, an ingredient in retroviral cocktails used to treat HIV, might also have a role in preventing acute graft-vs.-host disease after allogeneic hematopoietic stem-cell transplantation.

Adding a 1-month course of maraviroc (Selzentry), an inhibitor of T-cell chemotaxis, to standard prophylaxis appeared to reduce the incidence of acute graft-vs.-host disease (GVHD) after allogeneic transplants in a single-center study of 38 adults with hematologic cancers, which was published online July 11 in the New England Journal of Medicine.

At the same time, maraviroc did not disrupt hematopoietic engraftment, raise the incidence of cancer recurrence, or increase infectious complications, said Dr. Ran Reshef of the Abramson Cancer Center and the division of hematology and oncology at the University of Pennsylvania, Philadelphia, and his associates.

Maraviroc is the first drug available in the class of chemokine (C-C motif) receptor 5 (CCR5) antagonists. It prevents the signaling of CCR5 and its ligands, "which have been implicated in the pathogenesis of GVHD and solid-organ rejection." CCR5 is crucial to lymphocyte recruitment to tissues involved in GVHD. Blockade of CCR5 protects against GVHD in mouse models, and human genetic studies have shown that certain polymorphisms in the gene that encodes CCR5 are protective against GVHD.

Currently, maraviroc is used in combination antiretroviral therapy for a subtype of HIV that uses only the CCR5 coreceptor to enter cells. "We hypothesized that CCR5 blockade with maraviroc early after allogeneic hematopoietic stem-cell transplantation might inhibit lymphocyte trafficking and decrease the incidence of acute GVHD," Dr. Reshef and his colleagues said (N. Engl. J. Med. 2012;367:135-45).

They conducted a phase I clinical trial to confirm that the established dose for HIV patients was safe, and achieved target drug levels in patients who have undergone reduced-intensity conditioning and stem-cell transplantation. The cohort included patients with acute myeloid leukemia, non-Hodgkin’s lymphoma, myelodysplastic syndromes, myeloproliferative disorder, chronic lymphocytic leukemia, aplastic anemia, multiple myeloma, Hodgkin’s lymphoma, and chronic myeloid leukemia.

All the study subjects received standard GVHD prophylaxis including oral tacrolimus and IV methotrexate, as well as standard antimicrobial prophylaxis with voriconazole, acyclovir, and trimethoprim-sulfamethoxazole.

Most of the study subjects were considered high risk for GVHD because of their age (68% were older than 60 years), donor-recipient HLA incompatibility, cancer severity, and heavy burden of comorbidity. "The anticipated incidence of acute GVHD in similar patients is typically more than 50%," the investigators noted.

After the dose-confirming study, the researchers then performed a phase II clinical trial evaluating 35 of the same patients. Maraviroc (300 mg) was given orally twice daily from 2 days before transplantation until day 30. The study subjects were followed for a median of 20 months (range, 14-35 months).

Engraftment was rapid, and maraviroc produced few toxic effects. "Administration of the drug was briefly suspended in 7 patients because of grade 3 abnormalities on liver-function testing (in 2 patients) or grade 3 or 4 mucositis (in 5). Liver-function abnormalities did not recur when the drug was restarted," Dr. Reshef and his associates said.

The primary end point – the cumulative incidence of GVHD at day 100 – was 14.7% for grade II-IV acute disease. Remarkably, there were no cases of GVHD involving the liver or gut.

Similarly, at 6 months GVHD remained largely confined to the skin, and involved the liver in only 2.9% of cases and the gut in only 8.8%. At this point the incidence of moderate disease was 23.6% and severe disease only 5.9%. In comparison, these rates at their institution typically are 38.5% and 21.9%, the researchers said.

In the subset of 11 patients who received stem cells from an HLA-matched sibling, there were no cases of acute GVHD at day 100 and no moderate to severe GVHD at 6 months.

Thus, cases of skin GVHD developed at the expected rates, but the absence of liver or gut GVHD lead to a low incidence of severe disease.

"The outcomes of this study are especially favorable considering the study population, which included older patients and a high proportion of matched unrelated donors and HLA-mismatched donors." In addition, almost half the study subjects had major coexisting illnesses.

Cumulative rates of relapse and death were not higher than expected for patients with these disease characteristics who were given reduced-intensity regimens, the authors said.

Because this was a single-center, phase-I/phase-II trial involving only 38 patients, "the value of maraviroc in lowering the rate of acute GVHD will need to be assessed in a prospective, randomized trial," Dr. Reshef and his colleagues added.

This study was supported by Pfizer, maker of maraviroc; the Leukemia and Lymphoma Society; the National Institutes of Health; the Abramson Cancer Center; the American Society of Hematology; and the American Society of Clinical Oncology. Dr. Reshef’s associates reported ties to Pfizer, Bristol-Myers Squibb, Celgene, and Millennium.

Maraviroc, an ingredient in retroviral cocktails used to treat HIV, might also have a role in preventing acute graft-vs.-host disease after allogeneic hematopoietic stem-cell transplantation.

Adding a 1-month course of maraviroc (Selzentry), an inhibitor of T-cell chemotaxis, to standard prophylaxis appeared to reduce the incidence of acute graft-vs.-host disease (GVHD) after allogeneic transplants in a single-center study of 38 adults with hematologic cancers, which was published online July 11 in the New England Journal of Medicine.

At the same time, maraviroc did not disrupt hematopoietic engraftment, raise the incidence of cancer recurrence, or increase infectious complications, said Dr. Ran Reshef of the Abramson Cancer Center and the division of hematology and oncology at the University of Pennsylvania, Philadelphia, and his associates.

Maraviroc is the first drug available in the class of chemokine (C-C motif) receptor 5 (CCR5) antagonists. It prevents the signaling of CCR5 and its ligands, "which have been implicated in the pathogenesis of GVHD and solid-organ rejection." CCR5 is crucial to lymphocyte recruitment to tissues involved in GVHD. Blockade of CCR5 protects against GVHD in mouse models, and human genetic studies have shown that certain polymorphisms in the gene that encodes CCR5 are protective against GVHD.

Currently, maraviroc is used in combination antiretroviral therapy for a subtype of HIV that uses only the CCR5 coreceptor to enter cells. "We hypothesized that CCR5 blockade with maraviroc early after allogeneic hematopoietic stem-cell transplantation might inhibit lymphocyte trafficking and decrease the incidence of acute GVHD," Dr. Reshef and his colleagues said (N. Engl. J. Med. 2012;367:135-45).

They conducted a phase I clinical trial to confirm that the established dose for HIV patients was safe, and achieved target drug levels in patients who have undergone reduced-intensity conditioning and stem-cell transplantation. The cohort included patients with acute myeloid leukemia, non-Hodgkin’s lymphoma, myelodysplastic syndromes, myeloproliferative disorder, chronic lymphocytic leukemia, aplastic anemia, multiple myeloma, Hodgkin’s lymphoma, and chronic myeloid leukemia.

All the study subjects received standard GVHD prophylaxis including oral tacrolimus and IV methotrexate, as well as standard antimicrobial prophylaxis with voriconazole, acyclovir, and trimethoprim-sulfamethoxazole.

Most of the study subjects were considered high risk for GVHD because of their age (68% were older than 60 years), donor-recipient HLA incompatibility, cancer severity, and heavy burden of comorbidity. "The anticipated incidence of acute GVHD in similar patients is typically more than 50%," the investigators noted.

After the dose-confirming study, the researchers then performed a phase II clinical trial evaluating 35 of the same patients. Maraviroc (300 mg) was given orally twice daily from 2 days before transplantation until day 30. The study subjects were followed for a median of 20 months (range, 14-35 months).

Engraftment was rapid, and maraviroc produced few toxic effects. "Administration of the drug was briefly suspended in 7 patients because of grade 3 abnormalities on liver-function testing (in 2 patients) or grade 3 or 4 mucositis (in 5). Liver-function abnormalities did not recur when the drug was restarted," Dr. Reshef and his associates said.

The primary end point – the cumulative incidence of GVHD at day 100 – was 14.7% for grade II-IV acute disease. Remarkably, there were no cases of GVHD involving the liver or gut.

Similarly, at 6 months GVHD remained largely confined to the skin, and involved the liver in only 2.9% of cases and the gut in only 8.8%. At this point the incidence of moderate disease was 23.6% and severe disease only 5.9%. In comparison, these rates at their institution typically are 38.5% and 21.9%, the researchers said.

In the subset of 11 patients who received stem cells from an HLA-matched sibling, there were no cases of acute GVHD at day 100 and no moderate to severe GVHD at 6 months.

Thus, cases of skin GVHD developed at the expected rates, but the absence of liver or gut GVHD lead to a low incidence of severe disease.

"The outcomes of this study are especially favorable considering the study population, which included older patients and a high proportion of matched unrelated donors and HLA-mismatched donors." In addition, almost half the study subjects had major coexisting illnesses.

Cumulative rates of relapse and death were not higher than expected for patients with these disease characteristics who were given reduced-intensity regimens, the authors said.

Because this was a single-center, phase-I/phase-II trial involving only 38 patients, "the value of maraviroc in lowering the rate of acute GVHD will need to be assessed in a prospective, randomized trial," Dr. Reshef and his colleagues added.

This study was supported by Pfizer, maker of maraviroc; the Leukemia and Lymphoma Society; the National Institutes of Health; the Abramson Cancer Center; the American Society of Hematology; and the American Society of Clinical Oncology. Dr. Reshef’s associates reported ties to Pfizer, Bristol-Myers Squibb, Celgene, and Millennium.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.

The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.

Courtesy of FDA

To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.

Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.

Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.

Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.

Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.

Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.

Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.

The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.

Courtesy of FDA

To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.

Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.

Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.

Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.

Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.

Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.

Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.

The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.

Courtesy of FDA

To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.

Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.

Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.

Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.

Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.

Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.

AMSTERDAM – Up to 43% of elderly patients with diffuse large B cell lymphoma might be spared radiotherapy for bulky disease, if research suggesting that there is no additional benefit when using a standard chemotherapy regimen is confirmed.

In a prospective study from Germany, patients who achieved a complete remission (CR) or complete remission unconfirmed (CRu) with R-CHOP-14 plus two subsequent doses of rituximab (Rituxan) gained no additional benefit in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS), compared with a historical prospective cohort.

Sara Freeman/IMNG Medical Media

However, patients who did not achieve a CR/CRu following the chemotherapy did appear to benefit from radiotherapy to bulky disease, with higher rates on all three measures in the RICOVER-60-No-Rx trial, a German High Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) trial,

"The role of radiotherapy in the treatment of aggressive non-Hodgkin’s lymphoma is rather unclear, especially in the rituximab era, where systemic chemotherapy has become highly effective," Dr. Gerhard Held said at the annual congress of the European Hematology Association.

"The question arises if a local therapeutic modality like radiotherapy provides benefit to patients or [if it is] just adding additional toxicity," Dr. Held of Saarland University Hospital, Homburg, Germany, added.

The RICOVER-60-No-Rx trial resulted from a protocol amendment of the previously reported RICOVER-60 trial conducted in elderly patients with diffuse large B-cell lymphoma (DLBCL). The latter involved more than 1,200 men and women with DLBCL who were aged 61-80 years.

RICOVER-60 had a 2x2 factorial design and compared six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone given for 14 days (CHOP-14) with or without additional rituximab (R-CHOP-14). Patients with extranodal or bulky disease, defined as a tumor of more than 7.5 cm in diameter, received additional involved-field radiotherapy of 36 Gy.

The trial’s results (Lancet Oncol. 2008;9:105-16) showed a clear benefit of adding rituximab to the CHOP-14 regimen. The aim of the RICOVER-60-No-Rx study was to look more specifically at the role of radiotherapy in patients who had received the chemotherapy regimen.

In total 166 patients received additional chemotherapy without radiotherapy after the protocol amendment, and outcome data on these patients were compared with data on 306 patients who had received R-CHOP-14 plus two additional doses of rituximab and radiotherapy to bulky disease in the RICOVER-60 trial.

Dr. Held reported that, compared with the RICOVER-60 population, those in the RICOVER-60-No-Rx trial were older (median age of 69 vs. 71 years, P = .018), more likely to have advanced (stage III/IV) disease (50% vs. 60%, P = .037), and have extranodal involvement (50% vs. 63%, P = .024). In contrast, patients in the RICOVER-60 study were more likely to have bulky disease (35 vs. 29%, P = .024).

After a median observation time of 39 months, EFS (80% vs. 54%; P = .001), PFS (88% vs. 62%; P less than .001), and OS (90% vs. 65%; P = .001) were initially higher when comparing the RICOVER-60 cohort with the RICOVER-No-Rx cohort. However, taking protocol violations and the differences in demographics into consideration, there was no difference in the three measures between the groups overall (3-year EFS and PFS: 84% vs. 75%; P = .430); OS (87% vs. 79%; P = .839). Only patients who had not adequately responded to R-CHOP 14 appeared to benefit.

This was a not a randomized investigation, Dr. Held noted, and so of course further clarification of the role of radiotherapy in DCLBL is needed. To that end, the DSHNHL UNFOLDER trial is underway; this trial is looking look at the use of radiotherapy to bulky lesions vs. observation after six cycles of treatment with R-CHOP-14 or R-CHOP 21.

Computed tomography rather than positron emission tomography was used to stage patients, Dr. Aaron Polliack, emeritus professor of hematology and former head of the lymphoma and leukemia unit at Hadassah University Hospital in Jerusalem, noted during discussion that followed.

The results of the current trial therefore warrant caution in their interpretation, suggested Dr. Polliack, who is editor in chief of the journal Leukemia and Lymphoma and not involved in the study. He further commented that no decision can truly be made on the value of radiotherapy in this clinical situation until further data from the UNFOLDER and other studies are available.

The RICOVER-60-No-Rx trial was supported by Deutsche Krebshilfe and the original RICOVER-60 trial by Roche. Dr. Held disclosed receiving travel grants from Roche. Dr. Polliack had no conflicts of interest.

AMSTERDAM – Up to 43% of elderly patients with diffuse large B cell lymphoma might be spared radiotherapy for bulky disease, if research suggesting that there is no additional benefit when using a standard chemotherapy regimen is confirmed.

In a prospective study from Germany, patients who achieved a complete remission (CR) or complete remission unconfirmed (CRu) with R-CHOP-14 plus two subsequent doses of rituximab (Rituxan) gained no additional benefit in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS), compared with a historical prospective cohort.

Sara Freeman/IMNG Medical Media

However, patients who did not achieve a CR/CRu following the chemotherapy did appear to benefit from radiotherapy to bulky disease, with higher rates on all three measures in the RICOVER-60-No-Rx trial, a German High Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) trial,

"The role of radiotherapy in the treatment of aggressive non-Hodgkin’s lymphoma is rather unclear, especially in the rituximab era, where systemic chemotherapy has become highly effective," Dr. Gerhard Held said at the annual congress of the European Hematology Association.

"The question arises if a local therapeutic modality like radiotherapy provides benefit to patients or [if it is] just adding additional toxicity," Dr. Held of Saarland University Hospital, Homburg, Germany, added.

The RICOVER-60-No-Rx trial resulted from a protocol amendment of the previously reported RICOVER-60 trial conducted in elderly patients with diffuse large B-cell lymphoma (DLBCL). The latter involved more than 1,200 men and women with DLBCL who were aged 61-80 years.

RICOVER-60 had a 2x2 factorial design and compared six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone given for 14 days (CHOP-14) with or without additional rituximab (R-CHOP-14). Patients with extranodal or bulky disease, defined as a tumor of more than 7.5 cm in diameter, received additional involved-field radiotherapy of 36 Gy.

The trial’s results (Lancet Oncol. 2008;9:105-16) showed a clear benefit of adding rituximab to the CHOP-14 regimen. The aim of the RICOVER-60-No-Rx study was to look more specifically at the role of radiotherapy in patients who had received the chemotherapy regimen.

In total 166 patients received additional chemotherapy without radiotherapy after the protocol amendment, and outcome data on these patients were compared with data on 306 patients who had received R-CHOP-14 plus two additional doses of rituximab and radiotherapy to bulky disease in the RICOVER-60 trial.

Dr. Held reported that, compared with the RICOVER-60 population, those in the RICOVER-60-No-Rx trial were older (median age of 69 vs. 71 years, P = .018), more likely to have advanced (stage III/IV) disease (50% vs. 60%, P = .037), and have extranodal involvement (50% vs. 63%, P = .024). In contrast, patients in the RICOVER-60 study were more likely to have bulky disease (35 vs. 29%, P = .024).

After a median observation time of 39 months, EFS (80% vs. 54%; P = .001), PFS (88% vs. 62%; P less than .001), and OS (90% vs. 65%; P = .001) were initially higher when comparing the RICOVER-60 cohort with the RICOVER-No-Rx cohort. However, taking protocol violations and the differences in demographics into consideration, there was no difference in the three measures between the groups overall (3-year EFS and PFS: 84% vs. 75%; P = .430); OS (87% vs. 79%; P = .839). Only patients who had not adequately responded to R-CHOP 14 appeared to benefit.

This was a not a randomized investigation, Dr. Held noted, and so of course further clarification of the role of radiotherapy in DCLBL is needed. To that end, the DSHNHL UNFOLDER trial is underway; this trial is looking look at the use of radiotherapy to bulky lesions vs. observation after six cycles of treatment with R-CHOP-14 or R-CHOP 21.

Computed tomography rather than positron emission tomography was used to stage patients, Dr. Aaron Polliack, emeritus professor of hematology and former head of the lymphoma and leukemia unit at Hadassah University Hospital in Jerusalem, noted during discussion that followed.

The results of the current trial therefore warrant caution in their interpretation, suggested Dr. Polliack, who is editor in chief of the journal Leukemia and Lymphoma and not involved in the study. He further commented that no decision can truly be made on the value of radiotherapy in this clinical situation until further data from the UNFOLDER and other studies are available.

The RICOVER-60-No-Rx trial was supported by Deutsche Krebshilfe and the original RICOVER-60 trial by Roche. Dr. Held disclosed receiving travel grants from Roche. Dr. Polliack had no conflicts of interest.

AMSTERDAM – Up to 43% of elderly patients with diffuse large B cell lymphoma might be spared radiotherapy for bulky disease, if research suggesting that there is no additional benefit when using a standard chemotherapy regimen is confirmed.

In a prospective study from Germany, patients who achieved a complete remission (CR) or complete remission unconfirmed (CRu) with R-CHOP-14 plus two subsequent doses of rituximab (Rituxan) gained no additional benefit in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS), compared with a historical prospective cohort.

Sara Freeman/IMNG Medical Media

However, patients who did not achieve a CR/CRu following the chemotherapy did appear to benefit from radiotherapy to bulky disease, with higher rates on all three measures in the RICOVER-60-No-Rx trial, a German High Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) trial,

"The role of radiotherapy in the treatment of aggressive non-Hodgkin’s lymphoma is rather unclear, especially in the rituximab era, where systemic chemotherapy has become highly effective," Dr. Gerhard Held said at the annual congress of the European Hematology Association.

"The question arises if a local therapeutic modality like radiotherapy provides benefit to patients or [if it is] just adding additional toxicity," Dr. Held of Saarland University Hospital, Homburg, Germany, added.

The RICOVER-60-No-Rx trial resulted from a protocol amendment of the previously reported RICOVER-60 trial conducted in elderly patients with diffuse large B-cell lymphoma (DLBCL). The latter involved more than 1,200 men and women with DLBCL who were aged 61-80 years.

RICOVER-60 had a 2x2 factorial design and compared six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone given for 14 days (CHOP-14) with or without additional rituximab (R-CHOP-14). Patients with extranodal or bulky disease, defined as a tumor of more than 7.5 cm in diameter, received additional involved-field radiotherapy of 36 Gy.

The trial’s results (Lancet Oncol. 2008;9:105-16) showed a clear benefit of adding rituximab to the CHOP-14 regimen. The aim of the RICOVER-60-No-Rx study was to look more specifically at the role of radiotherapy in patients who had received the chemotherapy regimen.

In total 166 patients received additional chemotherapy without radiotherapy after the protocol amendment, and outcome data on these patients were compared with data on 306 patients who had received R-CHOP-14 plus two additional doses of rituximab and radiotherapy to bulky disease in the RICOVER-60 trial.

Dr. Held reported that, compared with the RICOVER-60 population, those in the RICOVER-60-No-Rx trial were older (median age of 69 vs. 71 years, P = .018), more likely to have advanced (stage III/IV) disease (50% vs. 60%, P = .037), and have extranodal involvement (50% vs. 63%, P = .024). In contrast, patients in the RICOVER-60 study were more likely to have bulky disease (35 vs. 29%, P = .024).

After a median observation time of 39 months, EFS (80% vs. 54%; P = .001), PFS (88% vs. 62%; P less than .001), and OS (90% vs. 65%; P = .001) were initially higher when comparing the RICOVER-60 cohort with the RICOVER-No-Rx cohort. However, taking protocol violations and the differences in demographics into consideration, there was no difference in the three measures between the groups overall (3-year EFS and PFS: 84% vs. 75%; P = .430); OS (87% vs. 79%; P = .839). Only patients who had not adequately responded to R-CHOP 14 appeared to benefit.

This was a not a randomized investigation, Dr. Held noted, and so of course further clarification of the role of radiotherapy in DCLBL is needed. To that end, the DSHNHL UNFOLDER trial is underway; this trial is looking look at the use of radiotherapy to bulky lesions vs. observation after six cycles of treatment with R-CHOP-14 or R-CHOP 21.

Computed tomography rather than positron emission tomography was used to stage patients, Dr. Aaron Polliack, emeritus professor of hematology and former head of the lymphoma and leukemia unit at Hadassah University Hospital in Jerusalem, noted during discussion that followed.

The results of the current trial therefore warrant caution in their interpretation, suggested Dr. Polliack, who is editor in chief of the journal Leukemia and Lymphoma and not involved in the study. He further commented that no decision can truly be made on the value of radiotherapy in this clinical situation until further data from the UNFOLDER and other studies are available.

The RICOVER-60-No-Rx trial was supported by Deutsche Krebshilfe and the original RICOVER-60 trial by Roche. Dr. Held disclosed receiving travel grants from Roche. Dr. Polliack had no conflicts of interest.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

AMSTERDAM – Crizotinib has shown significant antitumor activity in adult patients with lymphomas that express the anaplastic lymphoma kinase gene and who were resistant to the effects of at least three lines of previous therapy.

During a compassionate use program, eight of nine patients with anaplastic lymphoma kinase (ALK)–positive lymphoma responded to crizotinib (Xalkori). Six patients had complete responses, and four achieved durable responses lasting more than 6 months.

Sara Freeman/IMNG Medical Media

These data mirror positive early results already seen in pediatric anaplastic large cell lymphoma (ALCL). Seven of eight children treated with crizotinib had complete and durable responses, investigators reported at the American Society of Clinical Oncology annual meeting.

"Clinically, ALK+ lymphomas are known for their aggressiveness," said Dr. Carlo Gambacorti-Passerini, who presented the adult findings June 17 at the annual congress of the European Hematology Association. These data give a strong signal that further investigation in ALK-positive lymphomas is warranted.

Crizotinib was approved by the Food and Drug Administration for the treatment of ALK-driven non–small cell lung cancer (NSCLC) last August, but these new data suggest that responses may be even better in these lymphoma patients.

"It looks like, compared to EMF4-ALK-positive non–small cell lung cancer, the responses are much more durable," observed Dr. Matthias Theobald of Medizinische Klinik und Poliklink in Mainz, Germany, who chaired the session in which the adult findings were presented.

"Why lung cancer patients only have a median duration of responses of 10-12 months is not very clear," responded Dr. Carlo Gambacorti-Passerini, professor of internal medicine at the University of Milan–Bicocca and director of the clinical research unit at S. Gerardo Hospital, both in Monza, Italy.

It is also not apparent why some patients with ALK-positive lymphoma initially benefit while others develop resistance with time. "The main issue here is that [nearly] everybody responds, but after 2-3 months we see a divide," Dr. Gambacorti-Passerini said.

Four men and five women aged between 20 and 56 years (median age, 31 years) received crizotinib at a dose of 250 mg twice daily as part of a compassionate protocol. Seven patients had ALCL, and two patients had diffuse large cell lymphoma according to WHO criteria.

The median number of previous lines of therapy they had collectively received was three, although some had received up to five prior chemotherapy regimens, three had undergone autologous bone marrow transplant, and one patient an allogenic bone marrow transplant. While on crizotinib, steroid use or the use of drugs with antineoplastic activity was not allowed.

The effects of crizotinib were carefully assessed via physical exam, examination of bone marrow aspirate, positron-emission tomography and computed tomography scans, and blood tests before treatment initiation and at monthly intervals for the first 3 months, then every 3 months for up to 2 years. Disease status was also evaluated according to standard RECIST criteria.

After a median follow-up of 8 months, six patients had achieved a complete response to crizotinib, lasting for 2, 5, 8, 13, 18, or 24 months or more, respectively. A further two patients had a partial response.

Dr. Gambacorti-Passerini reported responses to treatment were "very rapid," with alleviation of fever within 2-10 days and time to normalization of serum lactate dehydrogenase within a month.

Furthermore, three patients were still on treatment with crizotinib. Six patients had discontinued: one because of patient request and five because of disease progression. The patient who discontinued by request did so because of severe gastroparesis unrelated to crizotinib and after a planned stoppage of the drug for a stem cell transplant.

Importantly, overall survival at 24 months appears to be just over 40%.

The most common side effects and lab abnormalities were ocular flashes, which all nine patients experienced, but these were of grade 1 or 2 and usually a temporary effect; one patient each had a grade 1-2 peripheral edema, a grade 3 neutropenia, and a grade 2 liver function test abnormality.

"These data show that crizotinib was well tolerated in this population of heavily pretreated patients," Dr. Gambacorti-Passerini concluded. He noted that patients have been treated with crizotinib for 2 years or more, which is the longest anyone has received the drug.

"Now, crizotinib is being evaluated in a registration study, which will start after this compassionate use," he added. This international phase I study (NCT01121588) is currently enrolling patients, and there are also suggestions of using crizotinib as first-line treatment or in combination with other agents for ALK+ lymphomas.

Dr. Gambacorti-Passerini has received research funding from Pfizer, which supported the compassionate use program.

AMSTERDAM – Crizotinib has shown significant antitumor activity in adult patients with lymphomas that express the anaplastic lymphoma kinase gene and who were resistant to the effects of at least three lines of previous therapy.

During a compassionate use program, eight of nine patients with anaplastic lymphoma kinase (ALK)–positive lymphoma responded to crizotinib (Xalkori). Six patients had complete responses, and four achieved durable responses lasting more than 6 months.

Sara Freeman/IMNG Medical Media

These data mirror positive early results already seen in pediatric anaplastic large cell lymphoma (ALCL). Seven of eight children treated with crizotinib had complete and durable responses, investigators reported at the American Society of Clinical Oncology annual meeting.

"Clinically, ALK+ lymphomas are known for their aggressiveness," said Dr. Carlo Gambacorti-Passerini, who presented the adult findings June 17 at the annual congress of the European Hematology Association. These data give a strong signal that further investigation in ALK-positive lymphomas is warranted.

Crizotinib was approved by the Food and Drug Administration for the treatment of ALK-driven non–small cell lung cancer (NSCLC) last August, but these new data suggest that responses may be even better in these lymphoma patients.

"It looks like, compared to EMF4-ALK-positive non–small cell lung cancer, the responses are much more durable," observed Dr. Matthias Theobald of Medizinische Klinik und Poliklink in Mainz, Germany, who chaired the session in which the adult findings were presented.

"Why lung cancer patients only have a median duration of responses of 10-12 months is not very clear," responded Dr. Carlo Gambacorti-Passerini, professor of internal medicine at the University of Milan–Bicocca and director of the clinical research unit at S. Gerardo Hospital, both in Monza, Italy.

It is also not apparent why some patients with ALK-positive lymphoma initially benefit while others develop resistance with time. "The main issue here is that [nearly] everybody responds, but after 2-3 months we see a divide," Dr. Gambacorti-Passerini said.

Four men and five women aged between 20 and 56 years (median age, 31 years) received crizotinib at a dose of 250 mg twice daily as part of a compassionate protocol. Seven patients had ALCL, and two patients had diffuse large cell lymphoma according to WHO criteria.

The median number of previous lines of therapy they had collectively received was three, although some had received up to five prior chemotherapy regimens, three had undergone autologous bone marrow transplant, and one patient an allogenic bone marrow transplant. While on crizotinib, steroid use or the use of drugs with antineoplastic activity was not allowed.

The effects of crizotinib were carefully assessed via physical exam, examination of bone marrow aspirate, positron-emission tomography and computed tomography scans, and blood tests before treatment initiation and at monthly intervals for the first 3 months, then every 3 months for up to 2 years. Disease status was also evaluated according to standard RECIST criteria.

After a median follow-up of 8 months, six patients had achieved a complete response to crizotinib, lasting for 2, 5, 8, 13, 18, or 24 months or more, respectively. A further two patients had a partial response.

Dr. Gambacorti-Passerini reported responses to treatment were "very rapid," with alleviation of fever within 2-10 days and time to normalization of serum lactate dehydrogenase within a month.

Furthermore, three patients were still on treatment with crizotinib. Six patients had discontinued: one because of patient request and five because of disease progression. The patient who discontinued by request did so because of severe gastroparesis unrelated to crizotinib and after a planned stoppage of the drug for a stem cell transplant.

Importantly, overall survival at 24 months appears to be just over 40%.

The most common side effects and lab abnormalities were ocular flashes, which all nine patients experienced, but these were of grade 1 or 2 and usually a temporary effect; one patient each had a grade 1-2 peripheral edema, a grade 3 neutropenia, and a grade 2 liver function test abnormality.

"These data show that crizotinib was well tolerated in this population of heavily pretreated patients," Dr. Gambacorti-Passerini concluded. He noted that patients have been treated with crizotinib for 2 years or more, which is the longest anyone has received the drug.

"Now, crizotinib is being evaluated in a registration study, which will start after this compassionate use," he added. This international phase I study (NCT01121588) is currently enrolling patients, and there are also suggestions of using crizotinib as first-line treatment or in combination with other agents for ALK+ lymphomas.

Dr. Gambacorti-Passerini has received research funding from Pfizer, which supported the compassionate use program.

AMSTERDAM – Crizotinib has shown significant antitumor activity in adult patients with lymphomas that express the anaplastic lymphoma kinase gene and who were resistant to the effects of at least three lines of previous therapy.

During a compassionate use program, eight of nine patients with anaplastic lymphoma kinase (ALK)–positive lymphoma responded to crizotinib (Xalkori). Six patients had complete responses, and four achieved durable responses lasting more than 6 months.

Sara Freeman/IMNG Medical Media

These data mirror positive early results already seen in pediatric anaplastic large cell lymphoma (ALCL). Seven of eight children treated with crizotinib had complete and durable responses, investigators reported at the American Society of Clinical Oncology annual meeting.

"Clinically, ALK+ lymphomas are known for their aggressiveness," said Dr. Carlo Gambacorti-Passerini, who presented the adult findings June 17 at the annual congress of the European Hematology Association. These data give a strong signal that further investigation in ALK-positive lymphomas is warranted.

Crizotinib was approved by the Food and Drug Administration for the treatment of ALK-driven non–small cell lung cancer (NSCLC) last August, but these new data suggest that responses may be even better in these lymphoma patients.

"It looks like, compared to EMF4-ALK-positive non–small cell lung cancer, the responses are much more durable," observed Dr. Matthias Theobald of Medizinische Klinik und Poliklink in Mainz, Germany, who chaired the session in which the adult findings were presented.

"Why lung cancer patients only have a median duration of responses of 10-12 months is not very clear," responded Dr. Carlo Gambacorti-Passerini, professor of internal medicine at the University of Milan–Bicocca and director of the clinical research unit at S. Gerardo Hospital, both in Monza, Italy.

It is also not apparent why some patients with ALK-positive lymphoma initially benefit while others develop resistance with time. "The main issue here is that [nearly] everybody responds, but after 2-3 months we see a divide," Dr. Gambacorti-Passerini said.

Four men and five women aged between 20 and 56 years (median age, 31 years) received crizotinib at a dose of 250 mg twice daily as part of a compassionate protocol. Seven patients had ALCL, and two patients had diffuse large cell lymphoma according to WHO criteria.

The median number of previous lines of therapy they had collectively received was three, although some had received up to five prior chemotherapy regimens, three had undergone autologous bone marrow transplant, and one patient an allogenic bone marrow transplant. While on crizotinib, steroid use or the use of drugs with antineoplastic activity was not allowed.

The effects of crizotinib were carefully assessed via physical exam, examination of bone marrow aspirate, positron-emission tomography and computed tomography scans, and blood tests before treatment initiation and at monthly intervals for the first 3 months, then every 3 months for up to 2 years. Disease status was also evaluated according to standard RECIST criteria.

After a median follow-up of 8 months, six patients had achieved a complete response to crizotinib, lasting for 2, 5, 8, 13, 18, or 24 months or more, respectively. A further two patients had a partial response.

Dr. Gambacorti-Passerini reported responses to treatment were "very rapid," with alleviation of fever within 2-10 days and time to normalization of serum lactate dehydrogenase within a month.

Furthermore, three patients were still on treatment with crizotinib. Six patients had discontinued: one because of patient request and five because of disease progression. The patient who discontinued by request did so because of severe gastroparesis unrelated to crizotinib and after a planned stoppage of the drug for a stem cell transplant.

Importantly, overall survival at 24 months appears to be just over 40%.

The most common side effects and lab abnormalities were ocular flashes, which all nine patients experienced, but these were of grade 1 or 2 and usually a temporary effect; one patient each had a grade 1-2 peripheral edema, a grade 3 neutropenia, and a grade 2 liver function test abnormality.

"These data show that crizotinib was well tolerated in this population of heavily pretreated patients," Dr. Gambacorti-Passerini concluded. He noted that patients have been treated with crizotinib for 2 years or more, which is the longest anyone has received the drug.

"Now, crizotinib is being evaluated in a registration study, which will start after this compassionate use," he added. This international phase I study (NCT01121588) is currently enrolling patients, and there are also suggestions of using crizotinib as first-line treatment or in combination with other agents for ALK+ lymphomas.

Dr. Gambacorti-Passerini has received research funding from Pfizer, which supported the compassionate use program.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.