Lymphoma & Plasma Cell Disorders

It is ironic that as oncologists struggle to get the time-tested, “good old drugs,” which are less expensive but nevertheless essential for many standard chemotherapy regimens, some drug companies are coming out with extremely expensive new drugs. It seems that in their quest for conquering new markets and providing new drug indications, none is looking out for the interests of our patients. Oncologists are the strongest advocates for their patients, and it is important that we are proactive when it comes to addressing the extremely sensitive topic of drug shortages. New, prohibitively expensive drugs might make sense from a dollars-and-cents perspective, but not from the patient or oncologist perspective.

In a Commentary on page 277, my co-editor Debra Patt examines the causes of the drug shortages and offers some possible solutions for alleviating them...

*For a PDF of the full article, click on the link to the left of this introduction.

It is ironic that as oncologists struggle to get the time-tested, “good old drugs,” which are less expensive but nevertheless essential for many standard chemotherapy regimens, some drug companies are coming out with extremely expensive new drugs. It seems that in their quest for conquering new markets and providing new drug indications, none is looking out for the interests of our patients. Oncologists are the strongest advocates for their patients, and it is important that we are proactive when it comes to addressing the extremely sensitive topic of drug shortages. New, prohibitively expensive drugs might make sense from a dollars-and-cents perspective, but not from the patient or oncologist perspective.

In a Commentary on page 277, my co-editor Debra Patt examines the causes of the drug shortages and offers some possible solutions for alleviating them...

*For a PDF of the full article, click on the link to the left of this introduction.

It is ironic that as oncologists struggle to get the time-tested, “good old drugs,” which are less expensive but nevertheless essential for many standard chemotherapy regimens, some drug companies are coming out with extremely expensive new drugs. It seems that in their quest for conquering new markets and providing new drug indications, none is looking out for the interests of our patients. Oncologists are the strongest advocates for their patients, and it is important that we are proactive when it comes to addressing the extremely sensitive topic of drug shortages. New, prohibitively expensive drugs might make sense from a dollars-and-cents perspective, but not from the patient or oncologist perspective.

In a Commentary on page 277, my co-editor Debra Patt examines the causes of the drug shortages and offers some possible solutions for alleviating them...

*For a PDF of the full article, click on the link to the left of this introduction.

SANTA BARBARA, CALIF. – Ovarian cortex orthotransplantation has resulted in the live births of at least 21 babies to cancer survivors in Europe, where the technique was pioneered and is being refined, Dr. Antonio Pellicer reported at a meeting on in vitro fertilization and embryo transfer.

Unlike the freezing of oocytes or embryos to preserve potential fertility, which requires ovarian stimulation, the ovarian cortex can be harvested from a cancer patient without delay, permitting immediate initiation of chemotherapy and/or radiation therapy. The tissue is cryopreserved until the patient is in remission.

If cancer treatment results in premature ovarian failure and the patient wishes to become pregnant, her autologous ovarian cortex can then be reintroduced.

©tirc83/iStockphoto.com

Ovarian function generally resumes within 3-4 months, said Dr. Pellicer, professor of obstetrics and gynecology and dean of the medical school at the University of Valencia (Spain). Follicle stimulating hormone rates do not reach normal levels, but are sufficient in many cases for resumption of menses and pregnancy, either naturally or through assisted reproductive techniques.

The technique is currently believed to be safe for breast cancer patients and those with Hodgkin’s and non-Hodgkin’s lymphoma, based on histologic and immunologic evaluations of harvested ovarian tissue, Dr. Pellicer said at the meeting, which was sponsored by the University of California, Los Angeles.

It is considered unsafe for patients with leukemia, as metastatic cells might well circulate through the bloodstream to the ovaries. Because of its highly metastatic potential, Ewing’s sarcoma is also considered a contraindication for the procedure, according to Dr. Pellicer.

The technique offers hope, potentially, for prepubertal girls and adolescents with other types of cancer, as well as adult cancer patients, although much remains unknown about the viability and usefulness of the treatment, explained Dr. Pellicer.

At the Valencia Program of Fertility Preservation, more than 600 cancer patients from across Spain have undergone removal of the ovarian cortex around the time of diagnosis, said Dr. Pellicer.

He reported on results in 583 of those patients who were treated since 2005, 55% of whom had been diagnosed with breast cancer.

Regular menses and fertility were restored in some patients who received ovarian autografts, said Dr. Pellicer. In all, 16 pregnancies and 3 live births have occurred, some following in vitro fertilization and some following natural conception.

Those results, along with published studies from programs in France, Germany, Denmark, Belgium, and other countries, indicate that at least 21 and perhaps 23 or more live births have resulted from the technique.

The problem, as Dr. Pellicer sees it, is a lack of cohesive follow-up or evidence that would put those births into perspective.

"We don’t know the number of failed attempts," he said. "There are no registries. There are no real data. Are we doing something which is really helpful? Or are the unsuccessful cases more [typical] than the successful cases?"

"This is a concern to me," he said.

Responding to a question from an audience member, Dr. Pellicer acknowledged that the removal of one ovarian cortex prior to cancer treatment might diminish fertility potential rather than enhance it, because some cancer patients conceive naturally following remission.

Dr. Pellicer reported that he had no relevant financial relationships to disclose.

SANTA BARBARA, CALIF. – Ovarian cortex orthotransplantation has resulted in the live births of at least 21 babies to cancer survivors in Europe, where the technique was pioneered and is being refined, Dr. Antonio Pellicer reported at a meeting on in vitro fertilization and embryo transfer.

Unlike the freezing of oocytes or embryos to preserve potential fertility, which requires ovarian stimulation, the ovarian cortex can be harvested from a cancer patient without delay, permitting immediate initiation of chemotherapy and/or radiation therapy. The tissue is cryopreserved until the patient is in remission.

If cancer treatment results in premature ovarian failure and the patient wishes to become pregnant, her autologous ovarian cortex can then be reintroduced.

©tirc83/iStockphoto.com

Ovarian function generally resumes within 3-4 months, said Dr. Pellicer, professor of obstetrics and gynecology and dean of the medical school at the University of Valencia (Spain). Follicle stimulating hormone rates do not reach normal levels, but are sufficient in many cases for resumption of menses and pregnancy, either naturally or through assisted reproductive techniques.

The technique is currently believed to be safe for breast cancer patients and those with Hodgkin’s and non-Hodgkin’s lymphoma, based on histologic and immunologic evaluations of harvested ovarian tissue, Dr. Pellicer said at the meeting, which was sponsored by the University of California, Los Angeles.

It is considered unsafe for patients with leukemia, as metastatic cells might well circulate through the bloodstream to the ovaries. Because of its highly metastatic potential, Ewing’s sarcoma is also considered a contraindication for the procedure, according to Dr. Pellicer.

The technique offers hope, potentially, for prepubertal girls and adolescents with other types of cancer, as well as adult cancer patients, although much remains unknown about the viability and usefulness of the treatment, explained Dr. Pellicer.

At the Valencia Program of Fertility Preservation, more than 600 cancer patients from across Spain have undergone removal of the ovarian cortex around the time of diagnosis, said Dr. Pellicer.

He reported on results in 583 of those patients who were treated since 2005, 55% of whom had been diagnosed with breast cancer.

Regular menses and fertility were restored in some patients who received ovarian autografts, said Dr. Pellicer. In all, 16 pregnancies and 3 live births have occurred, some following in vitro fertilization and some following natural conception.

Those results, along with published studies from programs in France, Germany, Denmark, Belgium, and other countries, indicate that at least 21 and perhaps 23 or more live births have resulted from the technique.

The problem, as Dr. Pellicer sees it, is a lack of cohesive follow-up or evidence that would put those births into perspective.

"We don’t know the number of failed attempts," he said. "There are no registries. There are no real data. Are we doing something which is really helpful? Or are the unsuccessful cases more [typical] than the successful cases?"

"This is a concern to me," he said.

Responding to a question from an audience member, Dr. Pellicer acknowledged that the removal of one ovarian cortex prior to cancer treatment might diminish fertility potential rather than enhance it, because some cancer patients conceive naturally following remission.

Dr. Pellicer reported that he had no relevant financial relationships to disclose.

SANTA BARBARA, CALIF. – Ovarian cortex orthotransplantation has resulted in the live births of at least 21 babies to cancer survivors in Europe, where the technique was pioneered and is being refined, Dr. Antonio Pellicer reported at a meeting on in vitro fertilization and embryo transfer.

Unlike the freezing of oocytes or embryos to preserve potential fertility, which requires ovarian stimulation, the ovarian cortex can be harvested from a cancer patient without delay, permitting immediate initiation of chemotherapy and/or radiation therapy. The tissue is cryopreserved until the patient is in remission.

If cancer treatment results in premature ovarian failure and the patient wishes to become pregnant, her autologous ovarian cortex can then be reintroduced.

©tirc83/iStockphoto.com

Ovarian function generally resumes within 3-4 months, said Dr. Pellicer, professor of obstetrics and gynecology and dean of the medical school at the University of Valencia (Spain). Follicle stimulating hormone rates do not reach normal levels, but are sufficient in many cases for resumption of menses and pregnancy, either naturally or through assisted reproductive techniques.

The technique is currently believed to be safe for breast cancer patients and those with Hodgkin’s and non-Hodgkin’s lymphoma, based on histologic and immunologic evaluations of harvested ovarian tissue, Dr. Pellicer said at the meeting, which was sponsored by the University of California, Los Angeles.

It is considered unsafe for patients with leukemia, as metastatic cells might well circulate through the bloodstream to the ovaries. Because of its highly metastatic potential, Ewing’s sarcoma is also considered a contraindication for the procedure, according to Dr. Pellicer.

The technique offers hope, potentially, for prepubertal girls and adolescents with other types of cancer, as well as adult cancer patients, although much remains unknown about the viability and usefulness of the treatment, explained Dr. Pellicer.

At the Valencia Program of Fertility Preservation, more than 600 cancer patients from across Spain have undergone removal of the ovarian cortex around the time of diagnosis, said Dr. Pellicer.

He reported on results in 583 of those patients who were treated since 2005, 55% of whom had been diagnosed with breast cancer.

Regular menses and fertility were restored in some patients who received ovarian autografts, said Dr. Pellicer. In all, 16 pregnancies and 3 live births have occurred, some following in vitro fertilization and some following natural conception.

Those results, along with published studies from programs in France, Germany, Denmark, Belgium, and other countries, indicate that at least 21 and perhaps 23 or more live births have resulted from the technique.

The problem, as Dr. Pellicer sees it, is a lack of cohesive follow-up or evidence that would put those births into perspective.

"We don’t know the number of failed attempts," he said. "There are no registries. There are no real data. Are we doing something which is really helpful? Or are the unsuccessful cases more [typical] than the successful cases?"

"This is a concern to me," he said.

Responding to a question from an audience member, Dr. Pellicer acknowledged that the removal of one ovarian cortex prior to cancer treatment might diminish fertility potential rather than enhance it, because some cancer patients conceive naturally following remission.

Dr. Pellicer reported that he had no relevant financial relationships to disclose.

AMSTERDAM  – Ask a hematologist about the most serious quality of life issues for patients with multiple myeloma, and neuropathy typically tops the list. But fatigue, malaise, or muscle weakness was more often concerning to patients who answered a survey on treatment-related side effects.

Cancer patients and their physicians differ to a large extent in their perceptions of a treatment’s impact on quality of life, according to Eric Low, the founder and chief executive of Myeloma UK. Even caregivers with a clear view of day-to-day realities may not see the patients’ point of view.

Although the patients’ caregivers "will often have a more accurate insight into how the cancer is affecting patients than the patients themselves, patients put more emphasis on quality than on longevity of life," he observed, citing data from the United Kingdom and from Europe, with myeloma patients specifically.

Contradictions in how patients and practitioners perceive quality of life was a recurrent theme in talks by patient advocates at the recent annual congress of the European Hematology Association. They described efforts to give patients a stronger voice through Internet-based questionnaires, physician guidelines, and tools for quality of life (QoL) assessment.

"There is such a large difference in perception of quality of life and what doctors think of quality of life in practice of a therapy and symptoms of disease, and what patients perceive about their impact on quality of life and symptoms," said Jan Geissler, a cofounder of the CML [Chronic Myeloid Leukemia] Advocates Network and director of the EUPATI (European Patients’ Academy on Therapeutic Innovation).

For patients on therapy, the need "is not only survival, but includes a lot of factors including quality of life – including, let’s say, how to cope with the disease, psychological factors," added Mr. Geissler, a CML survivor.

Survey Pinpoints Discrepancies

In 2009, Myeloma Euronet – which recently changed its name to Myeloma Patients Europe – conducted a survey to look at the effects of treatment side effects and unmet patient needs in patients with multiple myeloma. The aim was to look at, and compare, the opinions of those affected by the disease, including family members and general caregivers, vs. those of the medical profession.

A total of 314 health care professionals – among them 217 hematologists, 15 medical oncologists, 8 hematologist-oncologists, 68 nurses, and 5 other professionals – from 43 countries took part.

Participants also included 173 patients with multiple myeloma from 17 countries, and 85 relatives and 2 caregivers participating on behalf of myeloma patients from 13 countries. The largest patient contingent came from Poland.

The findings were enlightening, Mr. Low said. Patients and health care providers viewed the potential negative impact of several treatment-related side effects on overall well-being very differently.

Among physicians and nurses (83% and 77%, respectively), neuropathy was most often cited as having a negative impact on a patients’ well-being.

This was followed by a broad category of fatigue/malaise/weakness/dizziness/somnolence/sedation/insomnia, which was cited more often by nurses (72%) than by physicians (60%).

For physicians, infection had the third most negative impact. It was cited by (56%), followed by pain (48%) and thrombotic events (47%). A majority (62%) of nurses put nausea and vomiting in the No. 3 spot, however, followed by pain (57%). Infections and effects on the stomach and/or colon were each cited by 47% of nurses.

Among patients, relatives, and caregivers, the treatment side effect most often cited as compromising daily life fell into the broad category of fatigue/malaise/weakness/dizziness/somnolence/sedation/insomnia. This was cited by 73% of patients and 70% of their relatives and caregivers.

Neuropathy ranked second in negative impact for patients (54%) but was cited less often (45%) by relatives and caregivers, who put effects on the stomach and/or colon in second place (55%). Whereas decreased body function followed as No. 3 in negative impact among patients (53%), hair loss was cited by 52% of relatives and caregivers.

There were also several treatment-related side effects that patients did not report to their doctor, perhaps because they felt uncomfortable to do so. These included sexual problems, diarrhea, constipation, gastrointestinal upsets, and psychological issues, among others.

"Patients often put on a brave face, don’t want to let the side down, and associate [having] a positive outlook with therapeutic benefit," observed Mr. Low.

Moreover, balancing efficacy against side effects is "not what drives the patient all the time," he said. What patients want from treatment is very individual; although some patients may want greater choice or involvement in making decisions about their care, others may not. Some may prefer convenience or fewer side effects; others may want maximum disease control and a long, durable remission.

"It’s important that doctors tweak out what the objectives are for each individual patient and try to facilitate these in terms of how they are managed, and what treatments options are available," Mr. Low said. Quality of life should be considered as much as clinical outcomes, he suggested.

RareConnect Gathers Patient-Reported Information

An initiative called RareConnect could help provide important information about the effects of treatment from the patient perspective. Run by the EURODIS (European Organization for Rare Diseases), and by the U.S.-based NORD (National Organization for Rare Disorders), RareConnect is a social network of rare-disease communities that offers users the opportunity to assess patient-reported quality of life via a series of Internet-based questionnaires.

"What we are trying to do is bring a certain sense of structure now to the way patients can report on outcomes, essentially," said Denis Costello, who is leading the RareConnect project on behalf of EURODIS.

A pilot project is underway in patients with myeloma, he added in an interview. The Internet-based tool involves a series of interactive questionnaires that patients answer at a minimum of once a week. The collected information will include when patients were diagnosed, what treatments they have used, and their sliding-scale ratings of any side effects they have experienced.

RareConnect also allows patients to see how they compare with the rest of the community, and they can discuss their condition with others who are in a similar situation.

To develop a patient-friendly tool with the right level of lightness has been challenging because physicians want it to follow the lines of the quality of life scales and currently available instruments, Mr. Costello said. Physicians "want to get statistically significant data, but patients, we know, are not going to fill in those kinds of questionnaires."

Ultimately, "we want to provide a tool to patients to help them better self-manage their own outcomes in conjunction with their [health care professional], because we feel that this tool can help the patient, and bring a new dynamism between patient and doctor," he explained.

"It’s about discussion, really," Mr. Costello added, noting that the tool could help patients be more aware of their treatment and how it may affect them. In myeloma, for example, it could help prevent patients’ stopping treatment too early and later suffering a relapse.

"We really want to empower patients to see that [perhaps] you need to stay on the treatment a bit longer, and sometimes you need to fight," he suggested. RareConnect and other similar initiatives could provide the starting evidence that patients need to discuss such issues with their doctor.

Measuring Quality of Life

The European Hematology Association’s Scientific Working Group on Quality of Life and Symptoms has just published guidelines on how to assess quality of life in patients with hematologic disorders. Aimed at the practicing hematologist, these guidelines cover hematological malignancies, as well as other blood conditions.

"As physicians, as researchers, we understand that we do have new treatment modalities; we are able to provide good quality of care, but it very important to have the patient perspective to know if we are doing everything in the right way," said Tatyana Ionova, Ph.D., professor of the Postgraduate Education Institute at the National Medical Surgical Center Northwestern Branch in St. Petersburg, Russian Federation.

"Sometimes we may have information about the success or benefit or risks of treatment only from the patient perspective. That is why we try to develop the instruments, [which are] standardized measures that are able to ask the patients about their physical, social, psychological well-being, about [their] symptoms," Dr. Ionova said.

The EHA guidelines on "Patient-Reported Outcomes in Hematology" recognize that there are differences between hematologic diseases in terms of the quality of life assessments that can be used, "because bone marrow transplantation is very different from ITP [immune thrombocytopenic purpura," Dr. Ionova noted.

So how should hematologists measure quality of life? "First, read the guidelines," she suggested. "Then, have some very simple training about the questionnaires and how to use them."

These questionnaires shouldn’t take very long to be completed by or with the patient, she added. The important thing is that quality of life is considered.

The Myeloma Euronet survey was made possible through an unrestricted grant from Ortho Biotech. All authors reported no relevant disclosures other than working for their respective organizations.

AMSTERDAM  – Ask a hematologist about the most serious quality of life issues for patients with multiple myeloma, and neuropathy typically tops the list. But fatigue, malaise, or muscle weakness was more often concerning to patients who answered a survey on treatment-related side effects.

Cancer patients and their physicians differ to a large extent in their perceptions of a treatment’s impact on quality of life, according to Eric Low, the founder and chief executive of Myeloma UK. Even caregivers with a clear view of day-to-day realities may not see the patients’ point of view.

Although the patients’ caregivers "will often have a more accurate insight into how the cancer is affecting patients than the patients themselves, patients put more emphasis on quality than on longevity of life," he observed, citing data from the United Kingdom and from Europe, with myeloma patients specifically.

Contradictions in how patients and practitioners perceive quality of life was a recurrent theme in talks by patient advocates at the recent annual congress of the European Hematology Association. They described efforts to give patients a stronger voice through Internet-based questionnaires, physician guidelines, and tools for quality of life (QoL) assessment.

"There is such a large difference in perception of quality of life and what doctors think of quality of life in practice of a therapy and symptoms of disease, and what patients perceive about their impact on quality of life and symptoms," said Jan Geissler, a cofounder of the CML [Chronic Myeloid Leukemia] Advocates Network and director of the EUPATI (European Patients’ Academy on Therapeutic Innovation).

For patients on therapy, the need "is not only survival, but includes a lot of factors including quality of life – including, let’s say, how to cope with the disease, psychological factors," added Mr. Geissler, a CML survivor.

Survey Pinpoints Discrepancies

In 2009, Myeloma Euronet – which recently changed its name to Myeloma Patients Europe – conducted a survey to look at the effects of treatment side effects and unmet patient needs in patients with multiple myeloma. The aim was to look at, and compare, the opinions of those affected by the disease, including family members and general caregivers, vs. those of the medical profession.

A total of 314 health care professionals – among them 217 hematologists, 15 medical oncologists, 8 hematologist-oncologists, 68 nurses, and 5 other professionals – from 43 countries took part.

Participants also included 173 patients with multiple myeloma from 17 countries, and 85 relatives and 2 caregivers participating on behalf of myeloma patients from 13 countries. The largest patient contingent came from Poland.

The findings were enlightening, Mr. Low said. Patients and health care providers viewed the potential negative impact of several treatment-related side effects on overall well-being very differently.

Among physicians and nurses (83% and 77%, respectively), neuropathy was most often cited as having a negative impact on a patients’ well-being.

This was followed by a broad category of fatigue/malaise/weakness/dizziness/somnolence/sedation/insomnia, which was cited more often by nurses (72%) than by physicians (60%).

For physicians, infection had the third most negative impact. It was cited by (56%), followed by pain (48%) and thrombotic events (47%). A majority (62%) of nurses put nausea and vomiting in the No. 3 spot, however, followed by pain (57%). Infections and effects on the stomach and/or colon were each cited by 47% of nurses.

Among patients, relatives, and caregivers, the treatment side effect most often cited as compromising daily life fell into the broad category of fatigue/malaise/weakness/dizziness/somnolence/sedation/insomnia. This was cited by 73% of patients and 70% of their relatives and caregivers.

Neuropathy ranked second in negative impact for patients (54%) but was cited less often (45%) by relatives and caregivers, who put effects on the stomach and/or colon in second place (55%). Whereas decreased body function followed as No. 3 in negative impact among patients (53%), hair loss was cited by 52% of relatives and caregivers.

There were also several treatment-related side effects that patients did not report to their doctor, perhaps because they felt uncomfortable to do so. These included sexual problems, diarrhea, constipation, gastrointestinal upsets, and psychological issues, among others.

"Patients often put on a brave face, don’t want to let the side down, and associate [having] a positive outlook with therapeutic benefit," observed Mr. Low.

Moreover, balancing efficacy against side effects is "not what drives the patient all the time," he said. What patients want from treatment is very individual; although some patients may want greater choice or involvement in making decisions about their care, others may not. Some may prefer convenience or fewer side effects; others may want maximum disease control and a long, durable remission.

"It’s important that doctors tweak out what the objectives are for each individual patient and try to facilitate these in terms of how they are managed, and what treatments options are available," Mr. Low said. Quality of life should be considered as much as clinical outcomes, he suggested.

RareConnect Gathers Patient-Reported Information

An initiative called RareConnect could help provide important information about the effects of treatment from the patient perspective. Run by the EURODIS (European Organization for Rare Diseases), and by the U.S.-based NORD (National Organization for Rare Disorders), RareConnect is a social network of rare-disease communities that offers users the opportunity to assess patient-reported quality of life via a series of Internet-based questionnaires.

"What we are trying to do is bring a certain sense of structure now to the way patients can report on outcomes, essentially," said Denis Costello, who is leading the RareConnect project on behalf of EURODIS.

A pilot project is underway in patients with myeloma, he added in an interview. The Internet-based tool involves a series of interactive questionnaires that patients answer at a minimum of once a week. The collected information will include when patients were diagnosed, what treatments they have used, and their sliding-scale ratings of any side effects they have experienced.

RareConnect also allows patients to see how they compare with the rest of the community, and they can discuss their condition with others who are in a similar situation.

To develop a patient-friendly tool with the right level of lightness has been challenging because physicians want it to follow the lines of the quality of life scales and currently available instruments, Mr. Costello said. Physicians "want to get statistically significant data, but patients, we know, are not going to fill in those kinds of questionnaires."

Ultimately, "we want to provide a tool to patients to help them better self-manage their own outcomes in conjunction with their [health care professional], because we feel that this tool can help the patient, and bring a new dynamism between patient and doctor," he explained.

"It’s about discussion, really," Mr. Costello added, noting that the tool could help patients be more aware of their treatment and how it may affect them. In myeloma, for example, it could help prevent patients’ stopping treatment too early and later suffering a relapse.

"We really want to empower patients to see that [perhaps] you need to stay on the treatment a bit longer, and sometimes you need to fight," he suggested. RareConnect and other similar initiatives could provide the starting evidence that patients need to discuss such issues with their doctor.

Measuring Quality of Life

The European Hematology Association’s Scientific Working Group on Quality of Life and Symptoms has just published guidelines on how to assess quality of life in patients with hematologic disorders. Aimed at the practicing hematologist, these guidelines cover hematological malignancies, as well as other blood conditions.

"As physicians, as researchers, we understand that we do have new treatment modalities; we are able to provide good quality of care, but it very important to have the patient perspective to know if we are doing everything in the right way," said Tatyana Ionova, Ph.D., professor of the Postgraduate Education Institute at the National Medical Surgical Center Northwestern Branch in St. Petersburg, Russian Federation.

"Sometimes we may have information about the success or benefit or risks of treatment only from the patient perspective. That is why we try to develop the instruments, [which are] standardized measures that are able to ask the patients about their physical, social, psychological well-being, about [their] symptoms," Dr. Ionova said.

The EHA guidelines on "Patient-Reported Outcomes in Hematology" recognize that there are differences between hematologic diseases in terms of the quality of life assessments that can be used, "because bone marrow transplantation is very different from ITP [immune thrombocytopenic purpura," Dr. Ionova noted.

So how should hematologists measure quality of life? "First, read the guidelines," she suggested. "Then, have some very simple training about the questionnaires and how to use them."

These questionnaires shouldn’t take very long to be completed by or with the patient, she added. The important thing is that quality of life is considered.

The Myeloma Euronet survey was made possible through an unrestricted grant from Ortho Biotech. All authors reported no relevant disclosures other than working for their respective organizations.

AMSTERDAM  – Ask a hematologist about the most serious quality of life issues for patients with multiple myeloma, and neuropathy typically tops the list. But fatigue, malaise, or muscle weakness was more often concerning to patients who answered a survey on treatment-related side effects.

Cancer patients and their physicians differ to a large extent in their perceptions of a treatment’s impact on quality of life, according to Eric Low, the founder and chief executive of Myeloma UK. Even caregivers with a clear view of day-to-day realities may not see the patients’ point of view.

Although the patients’ caregivers "will often have a more accurate insight into how the cancer is affecting patients than the patients themselves, patients put more emphasis on quality than on longevity of life," he observed, citing data from the United Kingdom and from Europe, with myeloma patients specifically.

Contradictions in how patients and practitioners perceive quality of life was a recurrent theme in talks by patient advocates at the recent annual congress of the European Hematology Association. They described efforts to give patients a stronger voice through Internet-based questionnaires, physician guidelines, and tools for quality of life (QoL) assessment.

"There is such a large difference in perception of quality of life and what doctors think of quality of life in practice of a therapy and symptoms of disease, and what patients perceive about their impact on quality of life and symptoms," said Jan Geissler, a cofounder of the CML [Chronic Myeloid Leukemia] Advocates Network and director of the EUPATI (European Patients’ Academy on Therapeutic Innovation).

For patients on therapy, the need "is not only survival, but includes a lot of factors including quality of life – including, let’s say, how to cope with the disease, psychological factors," added Mr. Geissler, a CML survivor.

Survey Pinpoints Discrepancies

In 2009, Myeloma Euronet – which recently changed its name to Myeloma Patients Europe – conducted a survey to look at the effects of treatment side effects and unmet patient needs in patients with multiple myeloma. The aim was to look at, and compare, the opinions of those affected by the disease, including family members and general caregivers, vs. those of the medical profession.

A total of 314 health care professionals – among them 217 hematologists, 15 medical oncologists, 8 hematologist-oncologists, 68 nurses, and 5 other professionals – from 43 countries took part.

Participants also included 173 patients with multiple myeloma from 17 countries, and 85 relatives and 2 caregivers participating on behalf of myeloma patients from 13 countries. The largest patient contingent came from Poland.

The findings were enlightening, Mr. Low said. Patients and health care providers viewed the potential negative impact of several treatment-related side effects on overall well-being very differently.

Among physicians and nurses (83% and 77%, respectively), neuropathy was most often cited as having a negative impact on a patients’ well-being.

This was followed by a broad category of fatigue/malaise/weakness/dizziness/somnolence/sedation/insomnia, which was cited more often by nurses (72%) than by physicians (60%).

For physicians, infection had the third most negative impact. It was cited by (56%), followed by pain (48%) and thrombotic events (47%). A majority (62%) of nurses put nausea and vomiting in the No. 3 spot, however, followed by pain (57%). Infections and effects on the stomach and/or colon were each cited by 47% of nurses.

Among patients, relatives, and caregivers, the treatment side effect most often cited as compromising daily life fell into the broad category of fatigue/malaise/weakness/dizziness/somnolence/sedation/insomnia. This was cited by 73% of patients and 70% of their relatives and caregivers.

Neuropathy ranked second in negative impact for patients (54%) but was cited less often (45%) by relatives and caregivers, who put effects on the stomach and/or colon in second place (55%). Whereas decreased body function followed as No. 3 in negative impact among patients (53%), hair loss was cited by 52% of relatives and caregivers.

There were also several treatment-related side effects that patients did not report to their doctor, perhaps because they felt uncomfortable to do so. These included sexual problems, diarrhea, constipation, gastrointestinal upsets, and psychological issues, among others.

"Patients often put on a brave face, don’t want to let the side down, and associate [having] a positive outlook with therapeutic benefit," observed Mr. Low.

Moreover, balancing efficacy against side effects is "not what drives the patient all the time," he said. What patients want from treatment is very individual; although some patients may want greater choice or involvement in making decisions about their care, others may not. Some may prefer convenience or fewer side effects; others may want maximum disease control and a long, durable remission.

"It’s important that doctors tweak out what the objectives are for each individual patient and try to facilitate these in terms of how they are managed, and what treatments options are available," Mr. Low said. Quality of life should be considered as much as clinical outcomes, he suggested.

RareConnect Gathers Patient-Reported Information

An initiative called RareConnect could help provide important information about the effects of treatment from the patient perspective. Run by the EURODIS (European Organization for Rare Diseases), and by the U.S.-based NORD (National Organization for Rare Disorders), RareConnect is a social network of rare-disease communities that offers users the opportunity to assess patient-reported quality of life via a series of Internet-based questionnaires.

"What we are trying to do is bring a certain sense of structure now to the way patients can report on outcomes, essentially," said Denis Costello, who is leading the RareConnect project on behalf of EURODIS.

A pilot project is underway in patients with myeloma, he added in an interview. The Internet-based tool involves a series of interactive questionnaires that patients answer at a minimum of once a week. The collected information will include when patients were diagnosed, what treatments they have used, and their sliding-scale ratings of any side effects they have experienced.

RareConnect also allows patients to see how they compare with the rest of the community, and they can discuss their condition with others who are in a similar situation.

To develop a patient-friendly tool with the right level of lightness has been challenging because physicians want it to follow the lines of the quality of life scales and currently available instruments, Mr. Costello said. Physicians "want to get statistically significant data, but patients, we know, are not going to fill in those kinds of questionnaires."

Ultimately, "we want to provide a tool to patients to help them better self-manage their own outcomes in conjunction with their [health care professional], because we feel that this tool can help the patient, and bring a new dynamism between patient and doctor," he explained.

"It’s about discussion, really," Mr. Costello added, noting that the tool could help patients be more aware of their treatment and how it may affect them. In myeloma, for example, it could help prevent patients’ stopping treatment too early and later suffering a relapse.

"We really want to empower patients to see that [perhaps] you need to stay on the treatment a bit longer, and sometimes you need to fight," he suggested. RareConnect and other similar initiatives could provide the starting evidence that patients need to discuss such issues with their doctor.

Measuring Quality of Life

The European Hematology Association’s Scientific Working Group on Quality of Life and Symptoms has just published guidelines on how to assess quality of life in patients with hematologic disorders. Aimed at the practicing hematologist, these guidelines cover hematological malignancies, as well as other blood conditions.

"As physicians, as researchers, we understand that we do have new treatment modalities; we are able to provide good quality of care, but it very important to have the patient perspective to know if we are doing everything in the right way," said Tatyana Ionova, Ph.D., professor of the Postgraduate Education Institute at the National Medical Surgical Center Northwestern Branch in St. Petersburg, Russian Federation.

"Sometimes we may have information about the success or benefit or risks of treatment only from the patient perspective. That is why we try to develop the instruments, [which are] standardized measures that are able to ask the patients about their physical, social, psychological well-being, about [their] symptoms," Dr. Ionova said.

The EHA guidelines on "Patient-Reported Outcomes in Hematology" recognize that there are differences between hematologic diseases in terms of the quality of life assessments that can be used, "because bone marrow transplantation is very different from ITP [immune thrombocytopenic purpura," Dr. Ionova noted.

So how should hematologists measure quality of life? "First, read the guidelines," she suggested. "Then, have some very simple training about the questionnaires and how to use them."

These questionnaires shouldn’t take very long to be completed by or with the patient, she added. The important thing is that quality of life is considered.

The Myeloma Euronet survey was made possible through an unrestricted grant from Ortho Biotech. All authors reported no relevant disclosures other than working for their respective organizations.

Carfilzomib, a second-generation proteasome inhibitor administered intravenously, has been approved to treat patients with refractory multiple myeloma, the Food and Drug Administration announced on July 20.

The indication specifies use in patients who have received at least two prior lines of therapy that included the first-generation proteasome inhibitor bortezomib (Velcade) and an immunomodulatory drug (IMiD), and who have evidence of disease progression on or within 60 days of completing the last therapy,

Bortezomib was approved in 2003, and is among the new agents credited with prolonging the lives of patients with multiple myeloma. Carfilzomib will be marketed as Kyprolis by Onyx Pharmaceuticals. In clinical trials, it was effective in patients who stopped responding to bortezomib and to IMiDs, and it also appeared to cause less peripheral neuropathy.

The prescribing information for carfilzomib states that approval was based on response rate, and that clinical benefit, such as improvement in survival or symptoms, "has not been verified."

Carfilzomib received an accelerated approval, based on clinical evidence that the treatment has an effect on a surrogate end point that is "reasonably likely to predict a clinical benefit to patients," according to the Food and Drug Administration. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.

Onyx announced that it has completed enrollment in a phase III confirmatory study.

The accelerated approval was based on a phase IIb study of 266 patients with relapsed or refractory multiple myeloma, previously treated with at least two therapies, including bortezomib and an IMiD – thalidomide or lenalidomide (Revlimid). The patients started treatment with carfilzomib (administered twice weekly for 3 weeks, followed by a rest period, in a 28-day cycle) a median of 5.4 years after the initial diagnosis.

The overall response rate (complete responses, very good partial responses, and partial responses combined) was 23%, and the median duration of response was almost 8 months. Most responses were partial (18%), but one patient had a complete response.

The most commonly reported adverse effects associated with treatment were anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia, which were reported in 30% or more of patients in the study, according to the FDA. Serious adverse events were heart failure and shortness of breath.

At a meeting in June, the FDA’s Oncologic Drugs Advisory Committee supported accelerated approval of the drug for this population, noting that there are few if any treatment options available for patients with end-stage multiple myeloma, and that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval.

The confirmatory study, an international phase III study known as the ASPIRE study, is evaluating the combination of lenalidomide and low-dose dexamethasone with or without carfilzomib in patients with relapsed multiple myeloma who have received one to three previous therapies, according to the statement from Onyx announcing the approval.

Other studies that are underway include a phase III study evaluating carfilzomib as a single treatment for patients with relapsed and refractory myeloma who have received three or more prior therapies (FOCUS trial), which the company said is designed to "facilitate" approvals worldwide.

Another study, the ENDEAVOR trial, is comparing the combination of carfilzomib and low-dose dexamethasone to the combination of bortezomib and low-dose dexamethasone, according to Onyx.

The FDA statement cited American Cancer Society estimates that 21,700 people will be diagnosed with multiple myeloma and 10,710 will die from the disease in 2012.

"We are encouraged by the continued progress in the development of drugs for multiple myeloma over the past decade, offering improved treatment of this disease," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a news release.

The Multiple Myeloma Research Foundation issued a statement commending the FDA and Onyx for making carfilzomib available to patients with multiple myeloma. The foundation and its affiliated clinical trials network, the Multiple Myeloma Research Consortium, had helped Onyx with the pivotal clinical trial.

Kathy Giusti, founder and chief executive officer of the groups, called the approval "an immensely important milestone for the multiple myeloma patient community, which continues to face significant unmet need in terms of safe and effective treatments for advanced disease. While we have seen tremendous progress in the past decade, multiple myeloma remains incurable," she said.

The carfilzomib prescribing information is available here.

Carfilzomib, a second-generation proteasome inhibitor administered intravenously, has been approved to treat patients with refractory multiple myeloma, the Food and Drug Administration announced on July 20.

The indication specifies use in patients who have received at least two prior lines of therapy that included the first-generation proteasome inhibitor bortezomib (Velcade) and an immunomodulatory drug (IMiD), and who have evidence of disease progression on or within 60 days of completing the last therapy,

Bortezomib was approved in 2003, and is among the new agents credited with prolonging the lives of patients with multiple myeloma. Carfilzomib will be marketed as Kyprolis by Onyx Pharmaceuticals. In clinical trials, it was effective in patients who stopped responding to bortezomib and to IMiDs, and it also appeared to cause less peripheral neuropathy.

The prescribing information for carfilzomib states that approval was based on response rate, and that clinical benefit, such as improvement in survival or symptoms, "has not been verified."

Carfilzomib received an accelerated approval, based on clinical evidence that the treatment has an effect on a surrogate end point that is "reasonably likely to predict a clinical benefit to patients," according to the Food and Drug Administration. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.

Onyx announced that it has completed enrollment in a phase III confirmatory study.

The accelerated approval was based on a phase IIb study of 266 patients with relapsed or refractory multiple myeloma, previously treated with at least two therapies, including bortezomib and an IMiD – thalidomide or lenalidomide (Revlimid). The patients started treatment with carfilzomib (administered twice weekly for 3 weeks, followed by a rest period, in a 28-day cycle) a median of 5.4 years after the initial diagnosis.

The overall response rate (complete responses, very good partial responses, and partial responses combined) was 23%, and the median duration of response was almost 8 months. Most responses were partial (18%), but one patient had a complete response.

The most commonly reported adverse effects associated with treatment were anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia, which were reported in 30% or more of patients in the study, according to the FDA. Serious adverse events were heart failure and shortness of breath.

At a meeting in June, the FDA’s Oncologic Drugs Advisory Committee supported accelerated approval of the drug for this population, noting that there are few if any treatment options available for patients with end-stage multiple myeloma, and that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval.

The confirmatory study, an international phase III study known as the ASPIRE study, is evaluating the combination of lenalidomide and low-dose dexamethasone with or without carfilzomib in patients with relapsed multiple myeloma who have received one to three previous therapies, according to the statement from Onyx announcing the approval.

Other studies that are underway include a phase III study evaluating carfilzomib as a single treatment for patients with relapsed and refractory myeloma who have received three or more prior therapies (FOCUS trial), which the company said is designed to "facilitate" approvals worldwide.

Another study, the ENDEAVOR trial, is comparing the combination of carfilzomib and low-dose dexamethasone to the combination of bortezomib and low-dose dexamethasone, according to Onyx.

The FDA statement cited American Cancer Society estimates that 21,700 people will be diagnosed with multiple myeloma and 10,710 will die from the disease in 2012.

"We are encouraged by the continued progress in the development of drugs for multiple myeloma over the past decade, offering improved treatment of this disease," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a news release.

The Multiple Myeloma Research Foundation issued a statement commending the FDA and Onyx for making carfilzomib available to patients with multiple myeloma. The foundation and its affiliated clinical trials network, the Multiple Myeloma Research Consortium, had helped Onyx with the pivotal clinical trial.

Kathy Giusti, founder and chief executive officer of the groups, called the approval "an immensely important milestone for the multiple myeloma patient community, which continues to face significant unmet need in terms of safe and effective treatments for advanced disease. While we have seen tremendous progress in the past decade, multiple myeloma remains incurable," she said.

The carfilzomib prescribing information is available here.

Carfilzomib, a second-generation proteasome inhibitor administered intravenously, has been approved to treat patients with refractory multiple myeloma, the Food and Drug Administration announced on July 20.

The indication specifies use in patients who have received at least two prior lines of therapy that included the first-generation proteasome inhibitor bortezomib (Velcade) and an immunomodulatory drug (IMiD), and who have evidence of disease progression on or within 60 days of completing the last therapy,

Bortezomib was approved in 2003, and is among the new agents credited with prolonging the lives of patients with multiple myeloma. Carfilzomib will be marketed as Kyprolis by Onyx Pharmaceuticals. In clinical trials, it was effective in patients who stopped responding to bortezomib and to IMiDs, and it also appeared to cause less peripheral neuropathy.

The prescribing information for carfilzomib states that approval was based on response rate, and that clinical benefit, such as improvement in survival or symptoms, "has not been verified."

Carfilzomib received an accelerated approval, based on clinical evidence that the treatment has an effect on a surrogate end point that is "reasonably likely to predict a clinical benefit to patients," according to the Food and Drug Administration. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.

Onyx announced that it has completed enrollment in a phase III confirmatory study.

The accelerated approval was based on a phase IIb study of 266 patients with relapsed or refractory multiple myeloma, previously treated with at least two therapies, including bortezomib and an IMiD – thalidomide or lenalidomide (Revlimid). The patients started treatment with carfilzomib (administered twice weekly for 3 weeks, followed by a rest period, in a 28-day cycle) a median of 5.4 years after the initial diagnosis.

The overall response rate (complete responses, very good partial responses, and partial responses combined) was 23%, and the median duration of response was almost 8 months. Most responses were partial (18%), but one patient had a complete response.

The most commonly reported adverse effects associated with treatment were anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia, which were reported in 30% or more of patients in the study, according to the FDA. Serious adverse events were heart failure and shortness of breath.

At a meeting in June, the FDA’s Oncologic Drugs Advisory Committee supported accelerated approval of the drug for this population, noting that there are few if any treatment options available for patients with end-stage multiple myeloma, and that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval.

The confirmatory study, an international phase III study known as the ASPIRE study, is evaluating the combination of lenalidomide and low-dose dexamethasone with or without carfilzomib in patients with relapsed multiple myeloma who have received one to three previous therapies, according to the statement from Onyx announcing the approval.

Other studies that are underway include a phase III study evaluating carfilzomib as a single treatment for patients with relapsed and refractory myeloma who have received three or more prior therapies (FOCUS trial), which the company said is designed to "facilitate" approvals worldwide.

Another study, the ENDEAVOR trial, is comparing the combination of carfilzomib and low-dose dexamethasone to the combination of bortezomib and low-dose dexamethasone, according to Onyx.

The FDA statement cited American Cancer Society estimates that 21,700 people will be diagnosed with multiple myeloma and 10,710 will die from the disease in 2012.

"We are encouraged by the continued progress in the development of drugs for multiple myeloma over the past decade, offering improved treatment of this disease," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a news release.

The Multiple Myeloma Research Foundation issued a statement commending the FDA and Onyx for making carfilzomib available to patients with multiple myeloma. The foundation and its affiliated clinical trials network, the Multiple Myeloma Research Consortium, had helped Onyx with the pivotal clinical trial.

Kathy Giusti, founder and chief executive officer of the groups, called the approval "an immensely important milestone for the multiple myeloma patient community, which continues to face significant unmet need in terms of safe and effective treatments for advanced disease. While we have seen tremendous progress in the past decade, multiple myeloma remains incurable," she said.

The carfilzomib prescribing information is available here.

Anemia drugs sold under the brand names of Procrit, Aranesp, and Epogen come under new and scathing scrutiny in an exclusive report published July 20 in the Washington Post.

The investigative article by Peter Whoriskey alleges that pharmaceutical giants Amgen and Johnson & Johnson "wildly overstated" benefits while understating potentially lethal side effects of these erythropoiesis-stimulating agents (ESAs).

While safety trials required by the Food and Drug Administration lagged for more than a decade, the companies successfully lobbied for a payment system that rewarded physicians for giving large doses of their high-priced drugs, according to the report.

Use of the drugs declined in recent years after studies showed higher mortality rates in patients given ESAs. Epoetin-alfa (Procrit and Epogen) and darbepoetin alfa (Aranesp) are used to treat anemia in patients undergoing cancer chemotherapy or dialysis for chronic kidney disease.

Anemia drugs sold under the brand names of Procrit, Aranesp, and Epogen come under new and scathing scrutiny in an exclusive report published July 20 in the Washington Post.

The investigative article by Peter Whoriskey alleges that pharmaceutical giants Amgen and Johnson & Johnson "wildly overstated" benefits while understating potentially lethal side effects of these erythropoiesis-stimulating agents (ESAs).

While safety trials required by the Food and Drug Administration lagged for more than a decade, the companies successfully lobbied for a payment system that rewarded physicians for giving large doses of their high-priced drugs, according to the report.

Use of the drugs declined in recent years after studies showed higher mortality rates in patients given ESAs. Epoetin-alfa (Procrit and Epogen) and darbepoetin alfa (Aranesp) are used to treat anemia in patients undergoing cancer chemotherapy or dialysis for chronic kidney disease.

Anemia drugs sold under the brand names of Procrit, Aranesp, and Epogen come under new and scathing scrutiny in an exclusive report published July 20 in the Washington Post.

The investigative article by Peter Whoriskey alleges that pharmaceutical giants Amgen and Johnson & Johnson "wildly overstated" benefits while understating potentially lethal side effects of these erythropoiesis-stimulating agents (ESAs).

While safety trials required by the Food and Drug Administration lagged for more than a decade, the companies successfully lobbied for a payment system that rewarded physicians for giving large doses of their high-priced drugs, according to the report.

Use of the drugs declined in recent years after studies showed higher mortality rates in patients given ESAs. Epoetin-alfa (Procrit and Epogen) and darbepoetin alfa (Aranesp) are used to treat anemia in patients undergoing cancer chemotherapy or dialysis for chronic kidney disease.

CHICAGO – The novel antibody blinatumomab continues to induce high complete remission rates in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia.

In a phase II study with a dose-finding phase, 26 of 36 patients treated at various dose levels had a complete response (CR) or a complete response with partial hematologic recovery (CRh) within two treatment cycles, Dr. Max S. Topp reported at the annual meeting of the American Society of Clinical Oncology. Of 23 patients treated at the optimal dose, 17 had a CR or CRh, he said.

All but two of the patients with responses to the drug also had a molecular remission, he noted, and 13 patients went on to receive an allogeneic stem cell transplant after achieving a CR or CRh.

"We reached a very high rate of hematological and molecular remission in patients with blinatumomab," said Dr. Topp of the University of Würzburg (Germany).

The median duration of complete hematologic remission among all patients treated in the dose-finding phase was 8.9 months (median follow-up, 4.5 months). Median overall survival among patients treated at all dose levels was 9 months (median follow-up, 10.7 months).

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. It showed good activity in a phase I clinical trial in patients with relapsed non-Hodgkin’s lymphoma, as well as in a study of patients with B-lineage acute lymphoblastic leukemia (ALL) who were positive for minimal residual disease (J. Clin. Oncol. 2011;29:2493-8). Dr. Topp reported earlier results of the current MT103-206 study at the 2011 annual meeting of the American Society of Hematology.

The current trial was an open-label, multicenter phase II study of blinatumomab in patients with relapsed/refractory B-precursor ALL, or Philadelphia chromosome–positive ALL, who were ineligible for tyrosine kinase inhibitors or who were in relapse following an allogeneic stem cell transplant.

The trial had a dose-finding run-in phase with four patient cohorts. Dr. Topp provided updated outcomes data on cohorts 2a and 3 (the extension phase), in which patients received the selected dose schedule: an initial dose of 5 mcg/m² IV daily for the first week of cycle 1, followed by 15 mcg/m² per day for weeks 2-4 of every 4-week cycle, and every subsequent cycle. Patients had 2 weeks off between each cycle.

Patients who had a CR or CRh in the first two treatment cycles underwent consolidation with three additional cycles of blinatumomab and allogeneic stem cell transplant.

Medically important safety events to date include the cytokine release syndrome in three patients, two of whom had a high tumor burden with no cytoreductive prephase; and these patients required temporary treatment interruption. The third patient had a milder form of the syndrome and was managed with supportive medication, with no discontinuation of blinatumomab.

Six patients had central nervous system adverse events – three seizures and three cases of encephalopathy – that were reversible with treatment interruption. All six were eventually continued on the 5-mg/m² dose, but two had recurrence and permanently stopped treatment. One patient stopped because of a fungal infection that proved to be fatal.

Pyrexia, headache, tremor, and fatigue were the most common treatment-emergent adverse events, but there were only four grade 3 or higher reactions, including one increase in cytokine release syndrome. Most of the events occurred at the start of the first cycle.

The invited discussant, Dr. Bruno Medeiros of Stanford (Calif.) University, commented that blinatumomab appears to have good single-agent activity in relapsed or refractory ALL and is safe before allogeneic transplant. This agent, and another novel antibody against acute lymphocytic leukemia, inotuzumab, may also be effective when combined with chemotherapy or as single agents in first-line therapy, he said.

A global phase II study of blinatumomab in patients with relapsed or refractory ALL is underway.

The study was funded by Micromet, which has been acquired by Amgen. Dr. Topp disclosed having a consultant or advisory role and receiving other remuneration from Micromet. Dr. Medeiros disclosed ties with Millennium, Celgene, and Novartis.

CHICAGO – The novel antibody blinatumomab continues to induce high complete remission rates in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia.

In a phase II study with a dose-finding phase, 26 of 36 patients treated at various dose levels had a complete response (CR) or a complete response with partial hematologic recovery (CRh) within two treatment cycles, Dr. Max S. Topp reported at the annual meeting of the American Society of Clinical Oncology. Of 23 patients treated at the optimal dose, 17 had a CR or CRh, he said.

All but two of the patients with responses to the drug also had a molecular remission, he noted, and 13 patients went on to receive an allogeneic stem cell transplant after achieving a CR or CRh.

"We reached a very high rate of hematological and molecular remission in patients with blinatumomab," said Dr. Topp of the University of Würzburg (Germany).

The median duration of complete hematologic remission among all patients treated in the dose-finding phase was 8.9 months (median follow-up, 4.5 months). Median overall survival among patients treated at all dose levels was 9 months (median follow-up, 10.7 months).

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. It showed good activity in a phase I clinical trial in patients with relapsed non-Hodgkin’s lymphoma, as well as in a study of patients with B-lineage acute lymphoblastic leukemia (ALL) who were positive for minimal residual disease (J. Clin. Oncol. 2011;29:2493-8). Dr. Topp reported earlier results of the current MT103-206 study at the 2011 annual meeting of the American Society of Hematology.

The current trial was an open-label, multicenter phase II study of blinatumomab in patients with relapsed/refractory B-precursor ALL, or Philadelphia chromosome–positive ALL, who were ineligible for tyrosine kinase inhibitors or who were in relapse following an allogeneic stem cell transplant.

The trial had a dose-finding run-in phase with four patient cohorts. Dr. Topp provided updated outcomes data on cohorts 2a and 3 (the extension phase), in which patients received the selected dose schedule: an initial dose of 5 mcg/m² IV daily for the first week of cycle 1, followed by 15 mcg/m² per day for weeks 2-4 of every 4-week cycle, and every subsequent cycle. Patients had 2 weeks off between each cycle.

Patients who had a CR or CRh in the first two treatment cycles underwent consolidation with three additional cycles of blinatumomab and allogeneic stem cell transplant.

Medically important safety events to date include the cytokine release syndrome in three patients, two of whom had a high tumor burden with no cytoreductive prephase; and these patients required temporary treatment interruption. The third patient had a milder form of the syndrome and was managed with supportive medication, with no discontinuation of blinatumomab.

Six patients had central nervous system adverse events – three seizures and three cases of encephalopathy – that were reversible with treatment interruption. All six were eventually continued on the 5-mg/m² dose, but two had recurrence and permanently stopped treatment. One patient stopped because of a fungal infection that proved to be fatal.

Pyrexia, headache, tremor, and fatigue were the most common treatment-emergent adverse events, but there were only four grade 3 or higher reactions, including one increase in cytokine release syndrome. Most of the events occurred at the start of the first cycle.

The invited discussant, Dr. Bruno Medeiros of Stanford (Calif.) University, commented that blinatumomab appears to have good single-agent activity in relapsed or refractory ALL and is safe before allogeneic transplant. This agent, and another novel antibody against acute lymphocytic leukemia, inotuzumab, may also be effective when combined with chemotherapy or as single agents in first-line therapy, he said.

A global phase II study of blinatumomab in patients with relapsed or refractory ALL is underway.

The study was funded by Micromet, which has been acquired by Amgen. Dr. Topp disclosed having a consultant or advisory role and receiving other remuneration from Micromet. Dr. Medeiros disclosed ties with Millennium, Celgene, and Novartis.

CHICAGO – The novel antibody blinatumomab continues to induce high complete remission rates in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia.

In a phase II study with a dose-finding phase, 26 of 36 patients treated at various dose levels had a complete response (CR) or a complete response with partial hematologic recovery (CRh) within two treatment cycles, Dr. Max S. Topp reported at the annual meeting of the American Society of Clinical Oncology. Of 23 patients treated at the optimal dose, 17 had a CR or CRh, he said.

All but two of the patients with responses to the drug also had a molecular remission, he noted, and 13 patients went on to receive an allogeneic stem cell transplant after achieving a CR or CRh.

"We reached a very high rate of hematological and molecular remission in patients with blinatumomab," said Dr. Topp of the University of Würzburg (Germany).

The median duration of complete hematologic remission among all patients treated in the dose-finding phase was 8.9 months (median follow-up, 4.5 months). Median overall survival among patients treated at all dose levels was 9 months (median follow-up, 10.7 months).

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. It showed good activity in a phase I clinical trial in patients with relapsed non-Hodgkin’s lymphoma, as well as in a study of patients with B-lineage acute lymphoblastic leukemia (ALL) who were positive for minimal residual disease (J. Clin. Oncol. 2011;29:2493-8). Dr. Topp reported earlier results of the current MT103-206 study at the 2011 annual meeting of the American Society of Hematology.

The current trial was an open-label, multicenter phase II study of blinatumomab in patients with relapsed/refractory B-precursor ALL, or Philadelphia chromosome–positive ALL, who were ineligible for tyrosine kinase inhibitors or who were in relapse following an allogeneic stem cell transplant.

The trial had a dose-finding run-in phase with four patient cohorts. Dr. Topp provided updated outcomes data on cohorts 2a and 3 (the extension phase), in which patients received the selected dose schedule: an initial dose of 5 mcg/m² IV daily for the first week of cycle 1, followed by 15 mcg/m² per day for weeks 2-4 of every 4-week cycle, and every subsequent cycle. Patients had 2 weeks off between each cycle.

Patients who had a CR or CRh in the first two treatment cycles underwent consolidation with three additional cycles of blinatumomab and allogeneic stem cell transplant.

Medically important safety events to date include the cytokine release syndrome in three patients, two of whom had a high tumor burden with no cytoreductive prephase; and these patients required temporary treatment interruption. The third patient had a milder form of the syndrome and was managed with supportive medication, with no discontinuation of blinatumomab.

Six patients had central nervous system adverse events – three seizures and three cases of encephalopathy – that were reversible with treatment interruption. All six were eventually continued on the 5-mg/m² dose, but two had recurrence and permanently stopped treatment. One patient stopped because of a fungal infection that proved to be fatal.

Pyrexia, headache, tremor, and fatigue were the most common treatment-emergent adverse events, but there were only four grade 3 or higher reactions, including one increase in cytokine release syndrome. Most of the events occurred at the start of the first cycle.

The invited discussant, Dr. Bruno Medeiros of Stanford (Calif.) University, commented that blinatumomab appears to have good single-agent activity in relapsed or refractory ALL and is safe before allogeneic transplant. This agent, and another novel antibody against acute lymphocytic leukemia, inotuzumab, may also be effective when combined with chemotherapy or as single agents in first-line therapy, he said.

A global phase II study of blinatumomab in patients with relapsed or refractory ALL is underway.

The study was funded by Micromet, which has been acquired by Amgen. Dr. Topp disclosed having a consultant or advisory role and receiving other remuneration from Micromet. Dr. Medeiros disclosed ties with Millennium, Celgene, and Novartis.

CHICAGO – Long-term therapy with monthly zoledronic acid provides sustained survival benefits over daily oral bisphosphonates in multiple myeloma, with no evidence of a cumulative increase in the risk of osteonecrosis of the jaw.

After a median follow-up of 5.8 years in the MRC (U.K. Medical Research Council) Myeloma IX trial, zoledronic acid (Zometa) significantly improved the primary end points of progression-free survival (19 months vs. 18 months; hazard ratio, 0.88; P = .01) and overall survival (51 months vs. 46 months; HR, 0.88; P = .03) compared with oral clodronate. Patients in both arms of the trial received first-line intensive or nonintensive chemotherapy.

The overall cumulative incidence of osteonecrosis of the jaw (ONJ) was low, at 3.7% for zoledronic acid and 0.5% for clodronate (P less than .0001), Dr. Gareth J. Morgan reported at the annual meeting of the American Society of Clinical Oncology. ONJ is one of the most common reasons for discontinuing bisphosphonates, with previous reports’ linking the duration of exposure to its development.

"The first cases tend to occur by 12 months. These plateaued by about 36 months, and from that time on there is no continued cases or accrual of new cases," said Dr. Morgan, professor of hematology and head of the myeloma unit at Royal Marsden Hospital, London.

Session moderator Dr. Rafat Abonour, professor of medicine and director of adult clinical research in the cancer center at Indiana University, Indianapolis, said in an interview that IV bisphosphonates seem to be superior to oral ones, with less skeletal-related events and better survival.

"Survival is impressive," he said. "[The] low rate of ONJ is assuring that the benefit-risk ratio is in favor of using zoledronic acid."

The MRC Myeloma IX trial investigators previously reported significant progression-free and overall survival benefits for zoledronic acid over clodronate at 3.7 years’ follow-up (Lancet 2010;376:1965-6). They also found that zoledronic acid significantly reduces the risk of skeletal-related events, even among patients without bone lesions at baseline – a subset generally not considered for bisphosphonate therapy (Lancet Oncol. 2011;12:743-52).

Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated osteolysis, and are used along with chemotherapy to treat bone lesions present in about 70% of patients at diagnosis of multiple myeloma. The optimal duration of use, however, has not been determined.

The current data provide the longest follow-up from the MRC Myeloma IX trial, and further evidence that zoledronic acid also exerts an antimyeloma effect, said Dr. Morgan.

Investigators at 120 centers in the United Kingdom randomly assigned 1,960 patients with newly diagnosed stage I-III multiple myeloma to intravenous zoledronic acid at 4 mg every 21-28 days or oral 1,600 mg clodronate daily plus nonintensive chemotherapy consisting of oral melphalan and prednisone (MP) or attenuated oral cyclophosphamide, thalidomide and dexamethasone (C-TDa), or intensive chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or C-TD. After first-line treatment, patients were randomly assigned to maintenance therapy with thalidomide at 50 mg/day initially, increasing to 100 mg/day if tolerated, or to no thalidomide maintenance.

Renal failure rates ranged from 5% to 7% in the zoledronic group and from 6% to 7% in the clodronate group. ONJ rates ranged from 2% to 5% among zoledronate patients, compared with 0 to 1% for those who were given clodronate.

The study found that concomitant use of thalidomide seemed to reduce the rate of ONJ, Dr. Morgan noted. "This may reflect part of the mechanism of how ONJ occurs or it may relate to the fact that the responses are greater in the thalidomide-treated group," he added.

Among intensively treated zoledronic acid patients, ONJ rates fell significantly from 4.7% with CVAD to 3.2% with cyclophosphamide, thalidomide and dexamethasone (C-TD) chemotherapy. In the clodronate group, rates fell from 1.1% to 0%.

The same was true for nonintensively treated zoledronic acid patients, with ONJ rates decreasing significantly from 4.7% with melphalan and prednisone to 1.9% with attenuated C-TD, Dr. Morgan said. Rates for clodronate patients were 0.5% for both chemotherapy regimens.

Of note, thalidomide is used less in the United States. Furthermore, most U.S. oncologists use zoledronic acid and pamidronate (Aredia) rather than clodronate in the management of these patients.

Among nine zoledronic acid patients and one clodronate patient with ONJ recovery data, four had complete recovery, two improved, and four had no change, he said. Dental surgery or trauma preceded ONJ in six zoledronic patients.

The low ONJ incidence in the trial is likely due to the ONJ recommendations (Crit. Rev. Oncol. Hematol. 2007;62:148-152) that were disseminated to Myeloma IX investigators in June 2006, Dr. Morgan observed.

To reduce ONJ rates even further, he recommends that all patients receive a comprehensive dental examination before using bisphosphonates. Any unsalvageable teeth should be removed, all invasive dental procedures completed, and optimal periodontal health achieved.

The U.K. MRC funded the trial. Dr. Morgan reported honoraria and other relationships with Celgene, Johnson & Johnson, Merck, Novartis, and other companies. Dr. Abonour reported no conflicts of interest.

CHICAGO – Long-term therapy with monthly zoledronic acid provides sustained survival benefits over daily oral bisphosphonates in multiple myeloma, with no evidence of a cumulative increase in the risk of osteonecrosis of the jaw.

After a median follow-up of 5.8 years in the MRC (U.K. Medical Research Council) Myeloma IX trial, zoledronic acid (Zometa) significantly improved the primary end points of progression-free survival (19 months vs. 18 months; hazard ratio, 0.88; P = .01) and overall survival (51 months vs. 46 months; HR, 0.88; P = .03) compared with oral clodronate. Patients in both arms of the trial received first-line intensive or nonintensive chemotherapy.

The overall cumulative incidence of osteonecrosis of the jaw (ONJ) was low, at 3.7% for zoledronic acid and 0.5% for clodronate (P less than .0001), Dr. Gareth J. Morgan reported at the annual meeting of the American Society of Clinical Oncology. ONJ is one of the most common reasons for discontinuing bisphosphonates, with previous reports’ linking the duration of exposure to its development.

"The first cases tend to occur by 12 months. These plateaued by about 36 months, and from that time on there is no continued cases or accrual of new cases," said Dr. Morgan, professor of hematology and head of the myeloma unit at Royal Marsden Hospital, London.

Session moderator Dr. Rafat Abonour, professor of medicine and director of adult clinical research in the cancer center at Indiana University, Indianapolis, said in an interview that IV bisphosphonates seem to be superior to oral ones, with less skeletal-related events and better survival.

"Survival is impressive," he said. "[The] low rate of ONJ is assuring that the benefit-risk ratio is in favor of using zoledronic acid."

The MRC Myeloma IX trial investigators previously reported significant progression-free and overall survival benefits for zoledronic acid over clodronate at 3.7 years’ follow-up (Lancet 2010;376:1965-6). They also found that zoledronic acid significantly reduces the risk of skeletal-related events, even among patients without bone lesions at baseline – a subset generally not considered for bisphosphonate therapy (Lancet Oncol. 2011;12:743-52).

Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated osteolysis, and are used along with chemotherapy to treat bone lesions present in about 70% of patients at diagnosis of multiple myeloma. The optimal duration of use, however, has not been determined.

The current data provide the longest follow-up from the MRC Myeloma IX trial, and further evidence that zoledronic acid also exerts an antimyeloma effect, said Dr. Morgan.

Investigators at 120 centers in the United Kingdom randomly assigned 1,960 patients with newly diagnosed stage I-III multiple myeloma to intravenous zoledronic acid at 4 mg every 21-28 days or oral 1,600 mg clodronate daily plus nonintensive chemotherapy consisting of oral melphalan and prednisone (MP) or attenuated oral cyclophosphamide, thalidomide and dexamethasone (C-TDa), or intensive chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or C-TD. After first-line treatment, patients were randomly assigned to maintenance therapy with thalidomide at 50 mg/day initially, increasing to 100 mg/day if tolerated, or to no thalidomide maintenance.

Renal failure rates ranged from 5% to 7% in the zoledronic group and from 6% to 7% in the clodronate group. ONJ rates ranged from 2% to 5% among zoledronate patients, compared with 0 to 1% for those who were given clodronate.

The study found that concomitant use of thalidomide seemed to reduce the rate of ONJ, Dr. Morgan noted. "This may reflect part of the mechanism of how ONJ occurs or it may relate to the fact that the responses are greater in the thalidomide-treated group," he added.

Among intensively treated zoledronic acid patients, ONJ rates fell significantly from 4.7% with CVAD to 3.2% with cyclophosphamide, thalidomide and dexamethasone (C-TD) chemotherapy. In the clodronate group, rates fell from 1.1% to 0%.

The same was true for nonintensively treated zoledronic acid patients, with ONJ rates decreasing significantly from 4.7% with melphalan and prednisone to 1.9% with attenuated C-TD, Dr. Morgan said. Rates for clodronate patients were 0.5% for both chemotherapy regimens.

Of note, thalidomide is used less in the United States. Furthermore, most U.S. oncologists use zoledronic acid and pamidronate (Aredia) rather than clodronate in the management of these patients.

Among nine zoledronic acid patients and one clodronate patient with ONJ recovery data, four had complete recovery, two improved, and four had no change, he said. Dental surgery or trauma preceded ONJ in six zoledronic patients.

The low ONJ incidence in the trial is likely due to the ONJ recommendations (Crit. Rev. Oncol. Hematol. 2007;62:148-152) that were disseminated to Myeloma IX investigators in June 2006, Dr. Morgan observed.

To reduce ONJ rates even further, he recommends that all patients receive a comprehensive dental examination before using bisphosphonates. Any unsalvageable teeth should be removed, all invasive dental procedures completed, and optimal periodontal health achieved.

The U.K. MRC funded the trial. Dr. Morgan reported honoraria and other relationships with Celgene, Johnson & Johnson, Merck, Novartis, and other companies. Dr. Abonour reported no conflicts of interest.

CHICAGO – Long-term therapy with monthly zoledronic acid provides sustained survival benefits over daily oral bisphosphonates in multiple myeloma, with no evidence of a cumulative increase in the risk of osteonecrosis of the jaw.

After a median follow-up of 5.8 years in the MRC (U.K. Medical Research Council) Myeloma IX trial, zoledronic acid (Zometa) significantly improved the primary end points of progression-free survival (19 months vs. 18 months; hazard ratio, 0.88; P = .01) and overall survival (51 months vs. 46 months; HR, 0.88; P = .03) compared with oral clodronate. Patients in both arms of the trial received first-line intensive or nonintensive chemotherapy.

The overall cumulative incidence of osteonecrosis of the jaw (ONJ) was low, at 3.7% for zoledronic acid and 0.5% for clodronate (P less than .0001), Dr. Gareth J. Morgan reported at the annual meeting of the American Society of Clinical Oncology. ONJ is one of the most common reasons for discontinuing bisphosphonates, with previous reports’ linking the duration of exposure to its development.

"The first cases tend to occur by 12 months. These plateaued by about 36 months, and from that time on there is no continued cases or accrual of new cases," said Dr. Morgan, professor of hematology and head of the myeloma unit at Royal Marsden Hospital, London.

Session moderator Dr. Rafat Abonour, professor of medicine and director of adult clinical research in the cancer center at Indiana University, Indianapolis, said in an interview that IV bisphosphonates seem to be superior to oral ones, with less skeletal-related events and better survival.

"Survival is impressive," he said. "[The] low rate of ONJ is assuring that the benefit-risk ratio is in favor of using zoledronic acid."

The MRC Myeloma IX trial investigators previously reported significant progression-free and overall survival benefits for zoledronic acid over clodronate at 3.7 years’ follow-up (Lancet 2010;376:1965-6). They also found that zoledronic acid significantly reduces the risk of skeletal-related events, even among patients without bone lesions at baseline – a subset generally not considered for bisphosphonate therapy (Lancet Oncol. 2011;12:743-52).

Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated osteolysis, and are used along with chemotherapy to treat bone lesions present in about 70% of patients at diagnosis of multiple myeloma. The optimal duration of use, however, has not been determined.

The current data provide the longest follow-up from the MRC Myeloma IX trial, and further evidence that zoledronic acid also exerts an antimyeloma effect, said Dr. Morgan.

Investigators at 120 centers in the United Kingdom randomly assigned 1,960 patients with newly diagnosed stage I-III multiple myeloma to intravenous zoledronic acid at 4 mg every 21-28 days or oral 1,600 mg clodronate daily plus nonintensive chemotherapy consisting of oral melphalan and prednisone (MP) or attenuated oral cyclophosphamide, thalidomide and dexamethasone (C-TDa), or intensive chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or C-TD. After first-line treatment, patients were randomly assigned to maintenance therapy with thalidomide at 50 mg/day initially, increasing to 100 mg/day if tolerated, or to no thalidomide maintenance.

Renal failure rates ranged from 5% to 7% in the zoledronic group and from 6% to 7% in the clodronate group. ONJ rates ranged from 2% to 5% among zoledronate patients, compared with 0 to 1% for those who were given clodronate.

The study found that concomitant use of thalidomide seemed to reduce the rate of ONJ, Dr. Morgan noted. "This may reflect part of the mechanism of how ONJ occurs or it may relate to the fact that the responses are greater in the thalidomide-treated group," he added.

Among intensively treated zoledronic acid patients, ONJ rates fell significantly from 4.7% with CVAD to 3.2% with cyclophosphamide, thalidomide and dexamethasone (C-TD) chemotherapy. In the clodronate group, rates fell from 1.1% to 0%.

The same was true for nonintensively treated zoledronic acid patients, with ONJ rates decreasing significantly from 4.7% with melphalan and prednisone to 1.9% with attenuated C-TD, Dr. Morgan said. Rates for clodronate patients were 0.5% for both chemotherapy regimens.

Of note, thalidomide is used less in the United States. Furthermore, most U.S. oncologists use zoledronic acid and pamidronate (Aredia) rather than clodronate in the management of these patients.

Among nine zoledronic acid patients and one clodronate patient with ONJ recovery data, four had complete recovery, two improved, and four had no change, he said. Dental surgery or trauma preceded ONJ in six zoledronic patients.

The low ONJ incidence in the trial is likely due to the ONJ recommendations (Crit. Rev. Oncol. Hematol. 2007;62:148-152) that were disseminated to Myeloma IX investigators in June 2006, Dr. Morgan observed.

To reduce ONJ rates even further, he recommends that all patients receive a comprehensive dental examination before using bisphosphonates. Any unsalvageable teeth should be removed, all invasive dental procedures completed, and optimal periodontal health achieved.

The U.K. MRC funded the trial. Dr. Morgan reported honoraria and other relationships with Celgene, Johnson & Johnson, Merck, Novartis, and other companies. Dr. Abonour reported no conflicts of interest.

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.