Continuing patient access to innovative treatment options
Continuing patient access to innovative treatment options
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Submit your written public comments via your email
Submit your letterAlternatively, you can manually send an email to policydraft@noridian.com and moldx.policy@palmettogba.com with your message.
What is going on?
On August 10, 2023, MolDX issued a call for public comment on proposed changes to Medicare coverage policy (the local coverage determination (LCD)) which provides coverage guidance for the use of molecular testing (including donor-derived cell-free DNA) in solid organ transplant recipients. The purported rationale for the revisions is to provide clarity of coverage criteria without “change in coverage from the current Policy,” however, a close reading of the revisions suggests the new policy would have substantive coverage implications in two important areas for use in lung transplantation:
1. Frequency of Molecular Surveillance Testing
2. Concurrent Molecular Testing and Biopsy
Below, we review each in detail and describe how the new LCD may adversely impact clinical practice and patient care.
What is going on?
On August 10, 2023, MolDX issued a call for public comment on proposed changes to Medicare coverage policy (the local coverage determination (LCD)) which provides coverage guidance for the use of molecular testing (including donor-derived cell-free DNA) in solid organ transplant recipients. The purported rationale for the revisions is to provide clarity of coverage criteria without “change in coverage from the current Policy,” however, a close reading of the revisions suggests the new policy would have substantive coverage implications in two important areas for use in lung transplantation:
1. Frequency of Molecular Surveillance Testing
2. Concurrent Molecular Testing and Biopsy
Frequency of Molecular Surveillance Testing Limited by Biopsy Protocol
Lung transplant is utilized as a life saving measure in patients with end-stage lung disease. However, long-term survival after lung transplantation has lagged behind most other solid organ transplants with 5-year survival of only 54.3% (1). After the first post-transplant year, allograft failure in the form of chronic rejection or bronchiolitis obliterans syndrome (BOS) remains the most common cause of death (2). There has been ample evidence that acute cellular rejection (ACR) is associated with subsequent development of BOS (3, 4). As ACR can present with non-specific symptoms or be entirely asymptomatic (5), surveillance bronchoscopy and biopsies have been utilized in an effort to capture subclinical ACR by many lung transplant centers with varying frequencies(6) dependent on center and physician experience and patient need.
Transbronchial biopsies, while remaining the gold standard for diagnosis of ACR, are by nature invasive and not without complications. Reported complication rates have varied between 6-26% (5, 7-10) and can range from transient hypoxemia to need for mechanical ventilation, pneumothorax or even death. Moreover, there has been a sustained rise in lung transplant recipients that are advanced in age and with higher rates of comorbidities (11), which may result in additional complications. The presence of comorbidities also heightens the likelihood of having contraindications for biopsy. In addition, the reported 𝜅 coefficient for interobserver agreement has been disappointing, ranging from 0.18 to at best, 0.48 if only samples ≤ 6 weeks post-transplant were included (12, 13).
Donor-derived cell-free DNA (dd-cfDNA) has been validated in the lung transplant population to detect acute rejection as well as clinically significant infections (14-17). The utility of dd-cfDNA in the surveillance setting has been demonstrated most recently by Keller et al. in which dd-cfDNA was evaluated monthly within the first post-transplant year (17). Limiting the frequency of testing to center-specific protocol biopsies is flawed given the fundamentally disparate risk profile of a non-invasive blood test from an invasive procedure with known risks of complication. Center-specific surveillance biopsy schedules represent a desire to balance the utility of surveillance against the risks of an invasive procedure and logistic considerations such as travel time to a transplant center. Surveillance biopsy schedules, limited as described, should not be conflated with evidence-based surveillance interval of a noninvasive test.
Frequency of Molecular Surveillance Testing Limited by Biopsy Protocol
Lung transplant is utilized as a life saving measure in patients with end-stage lung disease. However, long-term survival after lung transplantation has lagged behind most other solid organ transplants with 5-year survival of only 54.3% (1). After the first post-transplant year, allograft failure in the form of chronic rejection or bronchiolitis obliterans syndrome (BOS) remains the most common cause of death (2). There has been ample evidence that acute cellular rejection (ACR) is associated with subsequent development of BOS (3, 4). As ACR can present with non-specific symptoms or be entirely asymptomatic (5), surveillance bronchoscopy and biopsies have been utilized in an effort to capture subclinical ACR by many lung transplant centers with varying frequencies(6) dependent on center and physician experience and patient need.
Transbronchial biopsies, while remaining the gold standard for diagnosis of ACR, are by nature invasive and not without complications. Reported complication rates have varied between 6-26% (5, 7-10) and can range from transient hypoxemia to need for mechanical ventilation, pneumothorax or even death. Moreover, there has been a sustained rise in lung transplant recipients that are advanced in age and with higher rates of comorbidities (11), which may result in additional complications. The presence of comorbidities also heightens the likelihood of having contraindications for biopsy. In addition, the reported 𝜅 coefficient for interobserver agreement has been disappointing, ranging from 0.18 to at best, 0.48 if only samples ≤ 6 weeks post-transplant were included (12, 13).
Donor-derived cell-free DNA (dd-cfDNA) has been validated in the lung transplant population to detect acute rejection as well as clinically significant infections (14-17). The utility of dd-cfDNA in the surveillance setting has been demonstrated most recently by Keller et al. in which dd-cfDNA was evaluated monthly within the first post-transplant year (17). Limiting the frequency of testing to center-specific protocol biopsies is flawed given the fundamentally disparate risk profile of a non-invasive blood test from an invasive procedure with known risks of complication. Center-specific surveillance biopsy schedules represent a desire to balance the utility of surveillance against the risks of an invasive procedure and logistic considerations such as travel time to a transplant center. Surveillance biopsy schedules, limited as described, should not be conflated with evidence-based surveillance interval of a noninvasive test.
Molecular Testing at the Time of Biopsy
Given the poor interobserver agreement with regards to histopathological diagnosis of acute rejection, considerable over- and under-treatment is to be expected. Indeed, Arcasoy et al. reported only 27% of grade A1 and 40% of ≥A2 rejection were associated with treatment in this multicenter observational study (12), likely at least in part due to the poor consensus between local and central pathologists.
Adding to the complexity, there are substantial variability between centers in the treatment of asymptomatic A1 rejection. While some advocate for treatment, a recent study by Levy et al. demonstrated no increased risk of CLAD (Chronic Lung Allograft Dysfunction) or death in lung transplant recipients with untreated spirometrically stable A1 rejection (18). It is reasonable to hypothesize that considering the sensitivity of dd-cfDNA in identifying tissue damage, the extent of elevation in dd-cfDNA levels might serve as a differentiating factor as demonstrated in kidney transplantation (19, 20). This differentiation may discern between histologic rejections warranting immediate treatment and those that might not necessitate intervention. dd- cfDNA adds an additional datapoint in the management of these challenging cases involving lung transplant recipients.
Molecular Testing at the Time of Biopsy
Given the poor interobserver agreement with regards to histopathological diagnosis of acute rejection, considerable over- and under-treatment is to be expected. Indeed, Arcasoy et al. reported only 27% of grade A1 and 40% of ≥A2 rejection were associated with treatment in this multicenter observational study (12), likely at least in part due to the poor consensus between local and central pathologists.
Adding to the complexity, there are substantial variability between centers in the treatment of asymptomatic A1 rejection. While some advocate for treatment, a recent study by Levy et al. demonstrated no increased risk of CLAD (Chronic Lung Allograft Dysfunction) or death in lung transplant recipients with untreated spirometrically stable A1 rejection (18). It is reasonable to hypothesize that considering the sensitivity of dd-cfDNA in identifying tissue damage, the extent of elevation in dd-cfDNA levels might serve as a differentiating factor as demonstrated in kidney transplantation (19, 20). This differentiation may discern between histologic rejections warranting immediate treatment and those that might not necessitate intervention. dd- cfDNA adds an additional datapoint in the management of these challenging cases involving lung transplant recipients.
Alternatively, you can manually send an email to policydraft@noridian.com and moldx.policy@palmettogba.com with your message
References
1. Valapour M, Lehr CJ, Schladt DP, Smith JM, Goff R, Mupfudze TG, Swanner K, Gauntt K, Snyder JJ. OPTN/SRTR 2021 Annual Data Report: Lung. Am J Transplant 2023; 23: S379-S442.
2. Transplantation ISfHaL. International Thoracic Organ Transplant Registry Data Slides. J Heart Lung Transplant 2019; 38: 1015-1066.
3. Bowdish ME, Arcasoy SM, Wilt JS, Conte JV, Davis RD, Garrity ER, Hertz ML, Orens JB, Rosengard BR, Barr ML. Surrogate markers and risk factors for chronic lung allograft dysfunction. Am J Transplant 2004; 4: 1171-1178.
4. Husain AN, Siddiqui MT, Holmes EW, Chandrasekhar AJ, McCabe M, Radvany R, Garrity ER. Analysis of risk factors for the development of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 1999; 159: 829-833.
5. McWilliams TJ, Williams TJ, Whitford HM, Snell GI. Surveillance bronchoscopy in lung transplant recipients: risk versus benefit. J Heart Lung Transplant 2008; 27: 1203-1209.
6. Martinu T, Koutsokera A, Benden C, Cantu E, Chambers D, Cypel M, Edelman J, Emtiazjoo A, Fisher AJ, Greenland JR, Hayes D, Jr., Hwang D, Keller BC, Lease ED, Perch M, Sato M, Todd JL, Verleden S, von der Thusen J, Weigt SS, Keshavjee S, bronchoalveolar lavage standardization w. International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation. J Heart Lung Transplant 2020; 39: 1171-1190.
7. Hopkins PM, Aboyoun CL, Chhajed PN, Malouf MA, Plit ML, Rainer SP, Glanville AR. Prospective analysis of 1,235 transbronchial lung biopsies in lung transplant recipients. J Heart Lung Transplant 2002; 21: 1062-1067.
8. Rademacher J, Suhling H, Greer M, Haverich A, Welte T, Warnecke G, Gottlieb J. Safety and efficacy of outpatient bronchoscopy in lung transplant recipients - a single centre analysis of 3,197 procedures. Transplant Res 2014; 3: 11.
9. Valentine VG, Gupta MR, Weill D, Lombard GA, LaPlace SG, Seoane L, Taylor DE, Dhillon GS. Single-institution study evaluating the utility of surveillance bronchoscopy after lung transplantation. J Heart Lung Transplant 2009; 28: 14-20.
10. Tosi D, Carrinola R, Morlacchi LC, Tarsia P, Rossetti V, Mendogni P, Rosso L, Righi I, Damarco F, Nosotti M. Surveillance Transbronchial Biopsy Program to Evaluate Acute Rejection After Lung Transplantation: A Single Institution Experience. Transplant Proc 2019; 51: 198-201.
11. Shigemura N, Toyoda Y. Elderly patients with multiple comorbidities: insights from the bedside to the bench and programmatic directions for this new challenge in lung transplantation. Transpl Int 2020; 33: 347-355.
12. Arcasoy SM, Berry G, Marboe CC, Tazelaar HD, Zamora MR, Wolters HJ, Fang KC, Keshavjee S. Pathologic interpretation of transbronchial biopsy for acute rejection of lung allograft is highly variable. Am J Transplant 2011; 11: 320-328.
13. Bhorade SM, Husain AN, Liao C, Li LC, Ahya VN, Baz MA, Valentine VG, Love RB, Seethamraju H, Alex CG, Bag R, DeOliveira NC, Vigneswaran WT, Garrity ER, Arcasoy SM. Interobserver variability in grading transbronchial lung biopsy specimens after lung transplantation. Chest 2013; 143: 1717-1724.
14. Sayah D, Weigt SS, Ramsey A, Ardehali A, Golden J, Ross DJ. Plasma Donor-derived Cell-free DNA Levels Are Increased During Acute Cellular Rejection After Lung Transplant: Pilot Data. Transplant Direct 2020; 6: e608.
15. Khush KK, De Vlaminck I, Luikart H, Ross DJ, Nicolls MR. Donor-derived, cell-free DNA levels by next-generation targeted sequencing are elevated in allograft rejection after lung transplantation. ERJ Open Res 2021; 7.
16. Levine DJ, Ross DJ, Sako E. Single Center "Snapshot" Experience With Donor-Derived Cell-Free DNA After Lung Transplantation. Biomark Insights 2020; 15: 1177271920958704.
17. Keller M, Sun J, Mutebi C, Shah P, Levine D, Aryal S, Iacono A, Timofte I, Mathew J, Varghese A, Giner C, Agbor-Enoh S. Donor-derived cell-free DNA as a composite marker of acute lung allograft dysfunction in clinical care. J Heart Lung Transplant 2022; 41: 458-466.
18. Levy L, Huszti E, Tikkanen J, Ghany R, Klement W, Ahmed M, Husain S, Fiset PO, Hwang D, Keshavjee S, Singer LG, Juvet S, Martinu T. The impact of first untreated subclinical minimal acute rejection on risk for chronic lung allograft dysfunction or death after lung transplantation. Am J Transplant 2020; 20: 241-249.
19. Rush D, Nickerson P, Gough J, McKenna R, Grimm P, Cheang M, Trpkov K, Solez K, Jeffery J. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 1998; 9: 2129-2134.
20. Stites E, Kumar D, Olaitan O, John Swanson S, Leca N, Weir M, Bromberg J, Melancon J, Agha I, Fattah H, Alhamad T, Qazi Y, Wiseman A, Gupta G. High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury. Am J Transplant 2020; 20: 2491-2498.
References
1. Valapour M, Lehr CJ, Schladt DP, Smith JM, Goff R, Mupfudze TG, Swanner K, Gauntt K, Snyder JJ. OPTN/SRTR 2021 Annual Data Report: Lung. Am J Transplant 2023; 23: S379-S442.
2. Transplantation ISfHaL. International Thoracic Organ Transplant Registry Data Slides. J Heart Lung Transplant 2019; 38: 1015-1066.
3. Bowdish ME, Arcasoy SM, Wilt JS, Conte JV, Davis RD, Garrity ER, Hertz ML, Orens JB, Rosengard BR, Barr ML. Surrogate markers and risk factors for chronic lung allograft dysfunction. Am J Transplant 2004; 4: 1171-1178.
4. Husain AN, Siddiqui MT, Holmes EW, Chandrasekhar AJ, McCabe M, Radvany R, Garrity ER. Analysis of risk factors for the development of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 1999; 159: 829-833.
5. McWilliams TJ, Williams TJ, Whitford HM, Snell GI. Surveillance bronchoscopy in lung transplant recipients: risk versus benefit. J Heart Lung Transplant 2008; 27: 1203-1209.
6. Martinu T, Koutsokera A, Benden C, Cantu E, Chambers D, Cypel M, Edelman J, Emtiazjoo A, Fisher AJ, Greenland JR, Hayes D, Jr., Hwang D, Keller BC, Lease ED, Perch M, Sato M, Todd JL, Verleden S, von der Thusen J, Weigt SS, Keshavjee S, bronchoalveolar lavage standardization w. International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation. J Heart Lung Transplant 2020; 39: 1171-1190.
7. Hopkins PM, Aboyoun CL, Chhajed PN, Malouf MA, Plit ML, Rainer SP, Glanville AR. Prospective analysis of 1,235 transbronchial lung biopsies in lung transplant recipients. J Heart Lung Transplant 2002; 21: 1062-1067.
8. Rademacher J, Suhling H, Greer M, Haverich A, Welte T, Warnecke G, Gottlieb J. Safety and efficacy of outpatient bronchoscopy in lung transplant recipients - a single centre analysis of 3,197 procedures. Transplant Res 2014; 3: 11.
9. Valentine VG, Gupta MR, Weill D, Lombard GA, LaPlace SG, Seoane L, Taylor DE, Dhillon GS. Single-institution study evaluating the utility of surveillance bronchoscopy after lung transplantation. J Heart Lung Transplant 2009; 28: 14-20.
10. Tosi D, Carrinola R, Morlacchi LC, Tarsia P, Rossetti V, Mendogni P, Rosso L, Righi I, Damarco F, Nosotti M. Surveillance Transbronchial Biopsy Program to Evaluate Acute Rejection After Lung Transplantation: A Single Institution Experience. Transplant Proc 2019; 51: 198-201.
11. Shigemura N, Toyoda Y. Elderly patients with multiple comorbidities: insights from the bedside to the bench and programmatic directions for this new challenge in lung transplantation. Transpl Int 2020; 33: 347-355.
12. Arcasoy SM, Berry G, Marboe CC, Tazelaar HD, Zamora MR, Wolters HJ, Fang KC, Keshavjee S. Pathologic interpretation of transbronchial biopsy for acute rejection of lung allograft is highly variable. Am J Transplant 2011; 11: 320-328.
13. Bhorade SM, Husain AN, Liao C, Li LC, Ahya VN, Baz MA, Valentine VG, Love RB, Seethamraju H, Alex CG, Bag R, DeOliveira NC, Vigneswaran WT, Garrity ER, Arcasoy SM. Interobserver variability in grading transbronchial lung biopsy specimens after lung transplantation. Chest 2013; 143: 1717-1724.
14. Sayah D, Weigt SS, Ramsey A, Ardehali A, Golden J, Ross DJ. Plasma Donor-derived Cell-free DNA Levels Are Increased During Acute Cellular Rejection After Lung Transplant: Pilot Data. Transplant Direct 2020; 6: e608.
15. Khush KK, De Vlaminck I, Luikart H, Ross DJ, Nicolls MR. Donor-derived, cell-free DNA levels by next-generation targeted sequencing are elevated in allograft rejection after lung transplantation. ERJ Open Res 2021; 7.
16. Levine DJ, Ross DJ, Sako E. Single Center "Snapshot" Experience With Donor-Derived Cell-Free DNA After Lung Transplantation. Biomark Insights 2020; 15: 1177271920958704.
17. Keller M, Sun J, Mutebi C, Shah P, Levine D, Aryal S, Iacono A, Timofte I, Mathew J, Varghese A, Giner C, Agbor-Enoh S. Donor-derived cell-free DNA as a composite marker of acute lung allograft dysfunction in clinical care. J Heart Lung Transplant 2022; 41: 458-466.
18. Levy L, Huszti E, Tikkanen J, Ghany R, Klement W, Ahmed M, Husain S, Fiset PO, Hwang D, Keshavjee S, Singer LG, Juvet S, Martinu T. The impact of first untreated subclinical minimal acute rejection on risk for chronic lung allograft dysfunction or death after lung transplantation. Am J Transplant 2020; 20: 241-249.
19. Rush D, Nickerson P, Gough J, McKenna R, Grimm P, Cheang M, Trpkov K, Solez K, Jeffery J. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 1998; 9: 2129-2134.
20. Stites E, Kumar D, Olaitan O, John Swanson S, Leca N, Weir M, Bromberg J, Melancon J, Agha I, Fattah H, Alhamad T, Qazi Y, Wiseman A, Gupta G. High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury. Am J Transplant 2020; 20: 2491-2498.