BY S UE PONDROM
News and issues that affect organ and tissue transplantation
Some experts support the use of the drug in transplantation, but it is expensive and others FKDOOHQJHLWVHI¿FDF\ everal studies support desensitization of immunologically disadvantaged transplant candidates with intravenous immunoglobulin (IVIg) therapy alone or in combination with other drugs, but many transplant centers decline to use this regimen due to its high cost, a percepWLRQRILQDGHTXDWHHI¿FDF\DQGRUWKHIHDUWKDW transplantation of high-risk patients will jeopardize outcomes.
S
High Cost The transplant team at Johns Hopkins in Baltimore has used an expensive IVIg preparation called Cytogam (CSL Behring, LLC). The group switched to Cytogam because they couldn’t get the most often used and less expensive IVIg products, says Robert Montgomery, MD, PhD, chief of the division of transplantation. ³1RZZH¶UH¿QDQFLDOO\JHWWLQJVTXHH]HGWR the point where we may need to go with standard IVIg, Gamunex [Grifols Therapeutics, Inc.]. It’s a big problem,” he says. He adds that “there is not consistency across the country in terms of payers, whether they are willing to pay for [the drug] and whether the Centers for Medicare & Medicaid Services [CMS] is willing to pay for it.” In 2001, Dr. Montgomery presented his initial desensitization data to CMS and says “they were impressed with the early results.” However, rather than approve the drug nationDOO\&06GHFLGHGWROHDYHLWXSWRLQGLYLGXDO¿VFDOLQWHUPHGLDULHV to determine reimbursement. Ian Jamieson, vice president of Duke University Hospital in Durham, N.C., says their lung transplant program is also under pressure to reduce costs. “We were two deviations above expected costs, which are currently 11% higher than what they should be,” according to University Health System Consortium data. Additionally, the cost of IVIg has increased by 17% over the past year, and the cost of the drug continues to go up. As a consequence, Duke pulmonologist John M. Reynolds, MD, says the lung transplant team is considering acceptance of fewer desensitized patients in some known high-risk groups.
© Shutterstock.com
Cost Effectiveness While admitting that the drug is not inexpensive, Stanley Jordan, MD, director of nephrology and kidney transplantation at Cedars Sinai Medical Center in Los Angeles and a leader in the use of IVIg in transplantation, says that it’s the hospitals that send out
Efficacy Questioned While many studies have supported the use of IVIg in desensitization, other research has quesWLRQHGLWVHI¿FDF\$UHFHQWVWXG\SXEOLVKHGLQ American Journal of Transplantation found that “an aggressive multi-modal desensitization SURWRFROGRHVQRWVLJQL¿FDQWO\UHGXFHSUHWUDQVplant HLA antibodies in a broadly sensitized lung transplant cohort.”3 A 2011 study determined that highly sensitized kidney patients with a calculated panel reactive antibody (CPRA) higher than 85% may QRWEHQH¿WIURPDFRPELQDWLRQRIULWX[LPDEDQG IVIg.4 The authors of a 2012 paper said that their study did not corroborate previous reports that CPRA reduction led to increased deceased-donor transplant rates with IVIg for desensitization.5 'U-RUGDQEHOLHYHVWKHQHJDWLYH¿QGLQJVDUH a matter of really understanding how the drugs work and what nuances to look for. “When calculating PRA with Luminex beads, you don’t see an effect because you can knock out several antibodies and still have a 90% CPRA,” he says. “One has to wait for a kidney to come along and do a crossmatch; then you see a difference in the level of certain antibodies that will allow the patient to get transplanted.”6 KEY POINTS • IVIg therapy is used in the desensitization of immunologically disadvantaged transplant candidates, although some question its economy, efficacy and outcomes. • IVIg can be costly, and faces worldwide shortages. • The drug’s limited availability has caused a U.S. team to develop and recommend a priority system for allocation.
A Regulatory Disincentive $QRWKHU¿QDQFLDOGHWHUUHQWWRWDNLQJRQFRPSOH[KLJKO\VHQVLtized patients is a regulatory disincentive. If a transplant center’s outcomes suffer due to highly sensitized patients, the center may EH³ÀDJJHG´E\WKH6FLHQWL¿F5HJLVWU\RI7UDQVSODQW5HFLSLHQWV (SRTR), and may lose CMS funding. Í
The IVIg Dilemma
exorbitant bills, sometimes 10 times the actual price of IVIg. ³7KRVHFKDUJHVGRQ¶WUHÀHFWWKHDFWXDOFRVW´KHVD\V Additionally, Dr. Jordan points out that in a comparison study of IVIg+rituzimab with dialysis, his team found that desensitization was more cost-effective than dialysis, and patients who were desensitized had an estimated 17.6% greater probability of three-year survival versus dialysis alone.12QHRIWKH¿UVWVWXGLHVWRVKRZWKH VXUYLYDOEHQH¿WRIGHVHQVLWL]DWLRQYHUVXVGLDO\VLVZDVSHUIRUPHG by Dr. Montgomery’s group in 2011.2 “What is the cost of human suffering and the cost the federal government pays for years and years of dialysis versus having a kidney transplant?” Dr. Jordan asks.
2195
(Continued from previous page)
“A couple of years ago we had a consensus conference in Washington, D.C., on how we should risk-adjust for programs that take high-risk patients,” says Bertram L. Kasiske, MD, project director of SRTR. The group came up with two possibilities: Take those patients entirely out of the analysis, or risk-adjust the model. However, according to Dr. Kasiske, SRTR has done neither regarding desensitization because current data from the Organ Procurement and Transplantation Network (OPTN) cannot accurately identify desensitized recipients, and removing recipients from the evaluation was found to be ill advised by both the SRTR Technical Advisory Committee and the OPTN Ad Hoc Committee on Program 6SHFL¿F5HSRUWV³:KHWKHURUQRWWRFROOHFW new data to add to risk adjustment models will likely be discussed by the OPTN’s new ad hoc Data Advisory Committee,” he adds.
VSHFL¿FUHSRUWVDVZHOODVULVNDGMXVWLQJ data for desensitization. However, he says, “The MPSC is not scheduled to hold further discussions on this, but that does not mean IXUWKHUGLVFXVVLRQVZLOOQRWRFFXU7KH¿QDO disposition will come from the OPTN.”
Prioritization Allocation For those who advocate IVIg usage, shortage of the product has become an issue. Pooled from the plasma of thousands of healthy human donors, IVIg is a commodity—an expensive one—with worldwide demand for a variety of diseases (see ³,9,J6&,J&RQVXPSWLRQ3HU&DSLWDLQ Selected Countries,” below). Because of the limited availability and fear of shortage, in 2007, the United Kingdom enacted the National Demand Management Programme for Immunoglobulin. The purpose was to set up a priority system that would designate values for medical condiIVIG/SCIG CONSUMPTION PER CAPITA tions requiring IVIg, IN SELECTED COUNTRIES - 2010 thus ensuring that (Grams per thousand inhabitants) supplies would be available to those at the top of the list. A group of American physicians is suggesting a similar allocation system for the U.S., which will be presented at the American Academy of Allergy, Asthma and Immunology (AAAI) meeting next February in HousSource: The Marketing Research Bureau, Inc. ton, Texas. Jordan Similarly, David Kappus, the OPTN Orange, MD, PhD, director of the Center for Membership and Professional Standards Human Immunobiology, Texas Children’s Committee (MPSC) liaison, says the Hospital at Baylor College of Medicine in committee has discussed exclusion of Houston, says that the proposed prioritizacertain high-risk patients from programtion algorithm is the result of three meet-
ings of a multispecialty group that hopes to obtain an expert perspective around the consideration on immunoglobulin therapy. “Most hospitals have a pharmacy and therapeutics committee, and almost one-third of institutions have a priority program in place, according to the IDF >,PPXQH'H¿FLHQF\)RXQGDWLRQ@VXUYH\ of hospital pharmacists,” says Dr. Orange. “However, these local decisions have potential for less balanced perspective.”
The New Kidney Allocation Policy Meanwhile, there is the new kidney allocation system to consider. Dr. Jordan says the allocation policy favors transplantation of highly sensitized patients. “We believe that with our desensitization protocols, we’ll be able to transplant a lot more of these patients, because they will be getting more offers,” he says. “If we turn our back on this population of highly sensitized patients, or make it very hard to transplant them, these patients will suffer.” References 1. Vo AA, Petrozzino J, Yeung K, Sinha A, Kahwaji J, Peng A, et al. Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab. Transplantation 2013; 95: 852-858. 2. Montgomery RA, Lonze BE, King KE, Krause ES, Kucirka LM, Locke JE, et al. Desensitization of HLAincompatible kidney recipients and survival. N Engl J Med 2011; 365: 318-326. 3. Snyder LD, Gray AL, Reynolds JM, Arepally GM, Bedoya A, Hartwig MG, et al. Antibody desensitization therapy in highly sensitized lung transplant candidates. Am J Transplant 2014; 14: 849-856. 4. Kozlowski T, Andreoni K. Limitations of rituximab/IVIg desensitization protocol in kidney transplantation; is this better than a tincture of time? Ann Transplant 2011; 16: 19-25. 5. Alachkar N, Lonze BE, Zachary AA, Holecheck MJ, Schillinger K, Cameron AM, et al. Infusion of highdose intravenous immunoglobulin fails to lower the strength of human leukocyte antigen antibodies in highly sensitized patients. Transplantation 2012; 94: 165-171. 6. Jordan SC, Vo A, Lai CH, Reinsmoen N. Defining the benefits of desensitization therapy. Transplantation 2013; 95: e31-e32.
Burnout Common Among Transplant Surgeons
T
ransplant surgeons report high levels of burnout due to interpersonal factors within the workplace, according to a study by researchers at the Henry Ford Health System in Detroit. Presented as a “Poster of Distinction” at the World Transplant Congress on July 30, 2014, in San Francisco, the study cited feelings of low personal accomplishment, an overextended work load and an unsupportive work environment as components of burnout. Michelle Jesse, PhD, senior staff psychologist at the Henry Ford
2196
Transplant Institute, led the study with Marwan Abouljoud, MD, director, and Anne Eshelman, PhD, senior staff psychologist. The team surveyed 218 American transplant surgeons, of whom 86.7% were men. A low sense of personal accomplishment was reported by 46.5% of surgeons; 40% noted a high level of emotional exhaustion. Only 17% expressed high levels of depersonalization, or emotional distancing from patients. Dr. Jesse says this indicates that transplant surgeons are extremely invested in and engaged with their patients.
But, she adds, they are frustrated by the process. Past studies of burnout have shown that contributing factors include those seen in the current study—ie, level of autonomy, case load, supportive work environment— but unique to the current study was patient interaction, Dr. Jesse says. “When surgeons reported they were uncomfortable with patient interactions, they reported depersonalization. Not so much the frequency of interaction, but how uncomfortable the surgeons were,” she says.
Co-presenter Dr. Abouljoud says that “burnout is common in medicine, especially in high-pressure specialties like transplantation. Organizations who employ those at increased risk for burnout should develop systems to prevent it and develop sustainable workforces.” Drs. Jesse, Abouljoud and Eshelman are working on an intervention tool kit that will first be available to physicians at the Henry Ford Health System, and then made available nationwide through transplant professional organizations.
American Journal of Transplantation 2014; 14: 2195-2196
News and issues that affect organ and tissue transplantation
Some experts support the use of the drug in transplantation, but it is expensive and others FKDOOHQJHLWVHI¿FDF\ everal studies support desensitization of immunologically disadvantaged transplant candidates with intravenous immunoglobulin (IVIg) therapy alone or in combination with other drugs, but many transplant centers decline to use this regimen due to its high cost, a percepWLRQRILQDGHTXDWHHI¿FDF\DQGRUWKHIHDUWKDW transplantation of high-risk patients will jeopardize outcomes.
S
High Cost The transplant team at Johns Hopkins in Baltimore has used an expensive IVIg preparation called Cytogam (CSL Behring, LLC). The group switched to Cytogam because they couldn’t get the most often used and less expensive IVIg products, says Robert Montgomery, MD, PhD, chief of the division of transplantation. ³1RZZH¶UH¿QDQFLDOO\JHWWLQJVTXHH]HGWR the point where we may need to go with standard IVIg, Gamunex [Grifols Therapeutics, Inc.]. It’s a big problem,” he says. He adds that “there is not consistency across the country in terms of payers, whether they are willing to pay for [the drug] and whether the Centers for Medicare & Medicaid Services [CMS] is willing to pay for it.” In 2001, Dr. Montgomery presented his initial desensitization data to CMS and says “they were impressed with the early results.” However, rather than approve the drug nationDOO\&06GHFLGHGWROHDYHLWXSWRLQGLYLGXDO¿VFDOLQWHUPHGLDULHV to determine reimbursement. Ian Jamieson, vice president of Duke University Hospital in Durham, N.C., says their lung transplant program is also under pressure to reduce costs. “We were two deviations above expected costs, which are currently 11% higher than what they should be,” according to University Health System Consortium data. Additionally, the cost of IVIg has increased by 17% over the past year, and the cost of the drug continues to go up. As a consequence, Duke pulmonologist John M. Reynolds, MD, says the lung transplant team is considering acceptance of fewer desensitized patients in some known high-risk groups.
© Shutterstock.com
Cost Effectiveness While admitting that the drug is not inexpensive, Stanley Jordan, MD, director of nephrology and kidney transplantation at Cedars Sinai Medical Center in Los Angeles and a leader in the use of IVIg in transplantation, says that it’s the hospitals that send out
Efficacy Questioned While many studies have supported the use of IVIg in desensitization, other research has quesWLRQHGLWVHI¿FDF\$UHFHQWVWXG\SXEOLVKHGLQ American Journal of Transplantation found that “an aggressive multi-modal desensitization SURWRFROGRHVQRWVLJQL¿FDQWO\UHGXFHSUHWUDQVplant HLA antibodies in a broadly sensitized lung transplant cohort.”3 A 2011 study determined that highly sensitized kidney patients with a calculated panel reactive antibody (CPRA) higher than 85% may QRWEHQH¿WIURPDFRPELQDWLRQRIULWX[LPDEDQG IVIg.4 The authors of a 2012 paper said that their study did not corroborate previous reports that CPRA reduction led to increased deceased-donor transplant rates with IVIg for desensitization.5 'U-RUGDQEHOLHYHVWKHQHJDWLYH¿QGLQJVDUH a matter of really understanding how the drugs work and what nuances to look for. “When calculating PRA with Luminex beads, you don’t see an effect because you can knock out several antibodies and still have a 90% CPRA,” he says. “One has to wait for a kidney to come along and do a crossmatch; then you see a difference in the level of certain antibodies that will allow the patient to get transplanted.”6 KEY POINTS • IVIg therapy is used in the desensitization of immunologically disadvantaged transplant candidates, although some question its economy, efficacy and outcomes. • IVIg can be costly, and faces worldwide shortages. • The drug’s limited availability has caused a U.S. team to develop and recommend a priority system for allocation.
A Regulatory Disincentive $QRWKHU¿QDQFLDOGHWHUUHQWWRWDNLQJRQFRPSOH[KLJKO\VHQVLtized patients is a regulatory disincentive. If a transplant center’s outcomes suffer due to highly sensitized patients, the center may EH³ÀDJJHG´E\WKH6FLHQWL¿F5HJLVWU\RI7UDQVSODQW5HFLSLHQWV (SRTR), and may lose CMS funding. Í
The IVIg Dilemma
exorbitant bills, sometimes 10 times the actual price of IVIg. ³7KRVHFKDUJHVGRQ¶WUHÀHFWWKHDFWXDOFRVW´KHVD\V Additionally, Dr. Jordan points out that in a comparison study of IVIg+rituzimab with dialysis, his team found that desensitization was more cost-effective than dialysis, and patients who were desensitized had an estimated 17.6% greater probability of three-year survival versus dialysis alone.12QHRIWKH¿UVWVWXGLHVWRVKRZWKH VXUYLYDOEHQH¿WRIGHVHQVLWL]DWLRQYHUVXVGLDO\VLVZDVSHUIRUPHG by Dr. Montgomery’s group in 2011.2 “What is the cost of human suffering and the cost the federal government pays for years and years of dialysis versus having a kidney transplant?” Dr. Jordan asks.
2195
(Continued from previous page)
“A couple of years ago we had a consensus conference in Washington, D.C., on how we should risk-adjust for programs that take high-risk patients,” says Bertram L. Kasiske, MD, project director of SRTR. The group came up with two possibilities: Take those patients entirely out of the analysis, or risk-adjust the model. However, according to Dr. Kasiske, SRTR has done neither regarding desensitization because current data from the Organ Procurement and Transplantation Network (OPTN) cannot accurately identify desensitized recipients, and removing recipients from the evaluation was found to be ill advised by both the SRTR Technical Advisory Committee and the OPTN Ad Hoc Committee on Program 6SHFL¿F5HSRUWV³:KHWKHURUQRWWRFROOHFW new data to add to risk adjustment models will likely be discussed by the OPTN’s new ad hoc Data Advisory Committee,” he adds.
VSHFL¿FUHSRUWVDVZHOODVULVNDGMXVWLQJ data for desensitization. However, he says, “The MPSC is not scheduled to hold further discussions on this, but that does not mean IXUWKHUGLVFXVVLRQVZLOOQRWRFFXU7KH¿QDO disposition will come from the OPTN.”
Prioritization Allocation For those who advocate IVIg usage, shortage of the product has become an issue. Pooled from the plasma of thousands of healthy human donors, IVIg is a commodity—an expensive one—with worldwide demand for a variety of diseases (see ³,9,J6&,J&RQVXPSWLRQ3HU&DSLWDLQ Selected Countries,” below). Because of the limited availability and fear of shortage, in 2007, the United Kingdom enacted the National Demand Management Programme for Immunoglobulin. The purpose was to set up a priority system that would designate values for medical condiIVIG/SCIG CONSUMPTION PER CAPITA tions requiring IVIg, IN SELECTED COUNTRIES - 2010 thus ensuring that (Grams per thousand inhabitants) supplies would be available to those at the top of the list. A group of American physicians is suggesting a similar allocation system for the U.S., which will be presented at the American Academy of Allergy, Asthma and Immunology (AAAI) meeting next February in HousSource: The Marketing Research Bureau, Inc. ton, Texas. Jordan Similarly, David Kappus, the OPTN Orange, MD, PhD, director of the Center for Membership and Professional Standards Human Immunobiology, Texas Children’s Committee (MPSC) liaison, says the Hospital at Baylor College of Medicine in committee has discussed exclusion of Houston, says that the proposed prioritizacertain high-risk patients from programtion algorithm is the result of three meet-
ings of a multispecialty group that hopes to obtain an expert perspective around the consideration on immunoglobulin therapy. “Most hospitals have a pharmacy and therapeutics committee, and almost one-third of institutions have a priority program in place, according to the IDF >,PPXQH'H¿FLHQF\)RXQGDWLRQ@VXUYH\ of hospital pharmacists,” says Dr. Orange. “However, these local decisions have potential for less balanced perspective.”
The New Kidney Allocation Policy Meanwhile, there is the new kidney allocation system to consider. Dr. Jordan says the allocation policy favors transplantation of highly sensitized patients. “We believe that with our desensitization protocols, we’ll be able to transplant a lot more of these patients, because they will be getting more offers,” he says. “If we turn our back on this population of highly sensitized patients, or make it very hard to transplant them, these patients will suffer.” References 1. Vo AA, Petrozzino J, Yeung K, Sinha A, Kahwaji J, Peng A, et al. Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab. Transplantation 2013; 95: 852-858. 2. Montgomery RA, Lonze BE, King KE, Krause ES, Kucirka LM, Locke JE, et al. Desensitization of HLAincompatible kidney recipients and survival. N Engl J Med 2011; 365: 318-326. 3. Snyder LD, Gray AL, Reynolds JM, Arepally GM, Bedoya A, Hartwig MG, et al. Antibody desensitization therapy in highly sensitized lung transplant candidates. Am J Transplant 2014; 14: 849-856. 4. Kozlowski T, Andreoni K. Limitations of rituximab/IVIg desensitization protocol in kidney transplantation; is this better than a tincture of time? Ann Transplant 2011; 16: 19-25. 5. Alachkar N, Lonze BE, Zachary AA, Holecheck MJ, Schillinger K, Cameron AM, et al. Infusion of highdose intravenous immunoglobulin fails to lower the strength of human leukocyte antigen antibodies in highly sensitized patients. Transplantation 2012; 94: 165-171. 6. Jordan SC, Vo A, Lai CH, Reinsmoen N. Defining the benefits of desensitization therapy. Transplantation 2013; 95: e31-e32.
Burnout Common Among Transplant Surgeons
T
ransplant surgeons report high levels of burnout due to interpersonal factors within the workplace, according to a study by researchers at the Henry Ford Health System in Detroit. Presented as a “Poster of Distinction” at the World Transplant Congress on July 30, 2014, in San Francisco, the study cited feelings of low personal accomplishment, an overextended work load and an unsupportive work environment as components of burnout. Michelle Jesse, PhD, senior staff psychologist at the Henry Ford
2196
Transplant Institute, led the study with Marwan Abouljoud, MD, director, and Anne Eshelman, PhD, senior staff psychologist. The team surveyed 218 American transplant surgeons, of whom 86.7% were men. A low sense of personal accomplishment was reported by 46.5% of surgeons; 40% noted a high level of emotional exhaustion. Only 17% expressed high levels of depersonalization, or emotional distancing from patients. Dr. Jesse says this indicates that transplant surgeons are extremely invested in and engaged with their patients.
But, she adds, they are frustrated by the process. Past studies of burnout have shown that contributing factors include those seen in the current study—ie, level of autonomy, case load, supportive work environment— but unique to the current study was patient interaction, Dr. Jesse says. “When surgeons reported they were uncomfortable with patient interactions, they reported depersonalization. Not so much the frequency of interaction, but how uncomfortable the surgeons were,” she says.
Co-presenter Dr. Abouljoud says that “burnout is common in medicine, especially in high-pressure specialties like transplantation. Organizations who employ those at increased risk for burnout should develop systems to prevent it and develop sustainable workforces.” Drs. Jesse, Abouljoud and Eshelman are working on an intervention tool kit that will first be available to physicians at the Henry Ford Health System, and then made available nationwide through transplant professional organizations.
American Journal of Transplantation 2014; 14: 2195-2196
