© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 776–782 DOI: 10.1111/ctr.12378
Clinical Transplantation
Lung transplantation following hematopoietic stem cell transplantation: report of two cases and systematic review of literature Soubani AO, Kingah P, Alshabani K, Muma G, Haq A. Lung transplantation following hematopoietic stem cell transplantation: report of two cases and systematic review of literature.
Ayman O. Soubania, Pascal Kingaha, Khaled Alshabania, Gilbert Mumab and Athar Haqa a
Abstract: Background: Non-infectious pulmonary complications following hematopoietic stem cell transplantation (HSCT) are major cause of morbidity and mortality with limited treatment options. Lung transplantation (LT) has been rarely reported as a treatment option for selected HSCT recipients with these problems. Objective: Describe the outcome of HSCT recipients who underwent LT. Methods: Two cases of LT following HSCT from our institution are presented. Cases reported in literature were identified using English language PubMed/MEDLINE with keywords hematopoietic stem cell transplantation, bone marrow transplantation, or bronchiolitis obliterans cross-referenced with lung transplantation. We extracted data on baseline characteristics and survival data following LT. Results: Total of 84 patients are analyzed. Age at time of LT was median of 22 yr (range 1–66). Seventy-nine patients were recipients of allogeneic HSCT. The indications for LT were bronchiolitis obliterans syndrome (BOS; 63 patients), pulmonary fibrosis (13 patients), BOS/pulmonary fibrosis (five patients), and graft-versus-host-disease (GVHD) of lung (three patients). The median time between HSCT and LT was 52.3 months (range 6–240). The median follow-up after LT was 36 months (range 0–168). During this time, BOS was documented in 25 patients. Relapse of hematological malignancy was reported in two patients, and new malignancy developed in four patients. At the end of follow-up, 60 patients were alive and 24 patients died. The probability of survival following LT at 24 and 36 months was 0.88 (95% CI 0.78–0.93) and 0.79 (95% CI 0.67–0.87), respectively. Conclusion: LT is a potential therapeutic option in selected patients with severe chronic pulmonary disease following HSCT. Further studies are needed to determine the appropriate timing and the outcome of this approach.
Hematopoietic stem cell transplantation (HSCT) is an important treatment for a variety of neoplastic, hematologic, and genetic conditions. The overall survival of HSCT recipients has been steadily improving (1). Pulmonary complications continue to be a major cause of morbidity and mortality in HSCT recipients (2). The recent advances in the diagnosis and management of infectious and early non-infectious pulmonary complications of HSCT increased the importance of late non-infectious conditions. These late complications are primarily represented by bronchiolitis obliterans syndrome
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Division of Pulmonary, Critical Care and Sleep Medicine, Karmanos Cancer Center, School of Medicine, Wayne State University, Detroit, MI, and bAstellas Pharma Inc, Chicago, IL, USA
Key words: bronchiolitis obliterans – hematopoietic stem cell transplantation – lung transplantation – outcome – survival Corresponding author: Ayman O. Soubani, MD, Division of Pulmonary, Critical Care and Sleep Medicine, School of Medicine, Wayne State University, 3990 John R-3 Hudson, Detroit, MI 48201, USA. Tel.: 313-966-0695; fax: 313-993-0562; e-mail: [email protected] Conflict of interest: None. Accepted for publication 21 April 2014
(BOS) and to a lesser degree pulmonary fibrosis and bronchiolitis obliterans organizing pneumonia (BOOP) (3). The reported prevalence of BOS following HSCT ranges between 2–5% and up to 14% in long-term survivors with chronic graft-versus-host-disease (GVHD) (4, 5). The mortality associated with BOS following HSCT reaches 60% (6). Medical management of BOS has been frustrating with limited success in stabilizing or reversing the progression of the disease (7). There is increasing number of reports about lung transplantation (LT) as a therapeutic option in selected
Lung transplantation following HSCT patients with BOS following HSCT. However, these reports are primarily based on single case or small case series. Furthermore, there is controversy about the optimal timing for LT, risk of relapse of underlying malignancy, and the survival of these patients following LT. In this report, we describe the clinical course of two HSCT recipients who underwent LT, then systematically review the literature to address these points. Methods
The objective of this study was to address three issues related to LT following HSCT. The first is what is the median time from HSCT to LT reported in the literature. The second issue is the survival of HSCT patients who underwent LT. The third is related to recurrence of underlying cancer or a secondary malignancy following LT in this patient population. For this purpose, we first report two patients from our institution who had allogeneic HSCT and later on underwent LT. Then, we searched the literature using PubMed/ MEDLINE with the keywords or text words “hematopoietic stem cell transplantation,” “bone marrow transplantation or bronchiolitis obliterans cross-referenced with lung transplantation.” We included only reports that were in English language and included adequate clinical details about the patients. Bibliography of these reports was also searched for additional cases. Every effort was made to make sure there were no duplications in the reporting of cases. The data extracted from these references included the age, gender, underlying illness, type of HSCT, the presence of GVHD, diagnosis of lung disease following HSCT, duration between HSCT and LT, type of LT, the presence of BOS following LT, recurrence of underlying disease prior to HSCT, or development of new malignancy. Also, we collected data on the outcome of these patients including the duration of survival following LT and from the original HSCT. These data were tabulated and analyzed. Institutional review board (IRB) approval was obtained to report the two cases. We used chi-square test to compare baseline characteristics for categorical variables and the ttest to compare baseline characteristics for continuous variables. Kaplan–Meier survival estimates were obtained and compared between some baseline characteristics. Log-rank test was used to determine statistical significance. Cox regression analysis was used to determine hazard ratios. Univariate analysis was performed initially, and modeling was considered if statistically significant differences were encountered. p-values of 18 yr) Gender (female vs. male) Duration between HSCT and LT (≤60 vs. >60 months) Type of HSCT (allogeneic vs. autologous) Type of LT (bilateral vs. single/lobar) Underlying lung disease prior to LT (BOS vs. fibrosis) Type of LT donor (cadaveric vs. live donor)
0.60 (0.27–1.37) 0.42 (0.17–1.0) 0.46 (0.19–1.0)
0.23 0.048 0.065
0.66 (0.19–3.83)
0.857
1.4 (0.56–3.6) 1.06 (0.53–2.15)
0.463 0.855
0.59 (0.22–1.60)
0.295
BOS, bronchiolitis obliterans syndrome; HSCT, hematopoietic stem cell transplantation; LT, lung transplantation.
Fig. 1). There was no significant difference in outcome between those patients who underwent bilateral vs. single/lobar LT (HR 1.4 [0.56 3.6, p = 0.463] Fig. 2). When comparing the outcome of patients who underwent LT before vs. after 60 months of HSCT, there was no significant difference in outcome between both groups (HR 0.46 [CI 0.19–1.00, p = 0.065]; Fig. 3). The causes of death were respiratory failure not otherwise specified (four patients), respiratory failure due to BOS or rejection (five patients), fungal infection (three patients—two specified as aspergillosis), CMV encephalitis (two patients), secondary malignancy (three patients, one with metastatic myoepithelial carcinoma of the mandible 104 months following LT, the second with esophageal cancer 30 months following LT, and the third with myxofibrosarcoma 24 months following LT), relapse of underlying hematologic malignancy (two patients—one patient with acute myeloid leukemia (AML) 13 months after LT, and the second patient with
Fig. 2. Cumulative probability of survival from time of lung transplant to end of study compared between single lung transplant and bilateral lung transplant recipients. There was no significant difference in outcome between the two groups during the reported follow-up period (p = 0.463).
Fig. 3. Cumulative probability of survival from time of lung transplant to end of study compared by duration between hematopoietic stem cell transplantation and lung transplantation of less than or more than 60 months (data available on 81 patients). There was no significant difference in outcome between the two groups during the reported follow-up period (p = 0.065).
myelodysplastic syndrome around 10 months following LT). Other causes of death included respiratory syncytial virus (RSV) pneumonia, septicemia, sepsis, multi-organ system failure, and pulmonary hemorrhage following lung biopsy (one patient each). One patient developed EBV-associated post-transplant lymphoproliferative disorder (PTLPD) that was successfully treated with involved field radiation and interferon therapy. The patient was alive five yr after LT. Discussion Fig. 1. Cumulative probability of survival from time of lung transplant to end of study compared between males and females. Females had better outcome during the follow-up period (p = 0.048).
This systematic review of the literature finds that LT was performed on 84 patients who underwent HSCT for a variety of malignancies. A total of 94% of these patients had allogeneic HSCT. The
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indication for LT was primarily BOS. A total of 76% of the patients had bilateral LT, and the majority were from cadaveric donor (81%). The LT were performed a median of 52.3 months following HSCT, and the patients were followed up a median of 36 months following LT. During this time, 2.5% of patients had relapse of underlying malignancy, 4.5% developed a new malignancy, and 28.6% of patients died. There were no significant predictors of survival during the follow-up period. One of the main controversies about performing LT following HSCT is the best timing of LT and risk of relapse of the underlying malignancy. The International Society for Heart and Lung Transplantation (ISHLT) recommends that LT should not be performed in the first two years after HSCT for malignant disease, and it is advisable to have five-yr disease-free interval prior to LT (29). In our analysis, the median time for LT was 52.3 months (range 6–240) following HSCT. When comparing the outcome of patients who underwent LT before vs. after 60 months of HSCT, there was no significant difference in outcome between both groups (HR 0.46 (CI 0.19–1.00, p = 0.065). Our analysis suggests that LT can be performed earlier than five yr following HSCT in selected patients and the overall outcome is not inferior to those who had the LT after five yr from HSCT. Relapse of underlying malignancy is a major concern following HSCT. The reported relapse rate following allogeneic HSCT in general has been in the range of 34–41% (30). This has been a major concern about performing LT in HSCT recipients. In our analysis, only two patients (2.4%) had relapse of the underlying hematologic malignancy during the follow-up period after LT. One patient had relapse of AML and the second relapse of myelodysplastic syndrome (MDS) 13 months and 10 months following LT, respectively. Similar findings were found in a study of 40 HSCT recipients who underwent a variety of solid organ transplants, only 4% had relapse of the underlying malignancy at five yr (23). It is possible that the presence of chronic GVHD in patients with history of HSCT has a protective role against relapse of underlying malignancy by exerting graft vs. leukemia effect. On the other hand, intensifying the immunosuppression following LT may increase the chances of malignancy relapse, especially with aggressive types of acute leukemia. The findings in this study suggest that relapse of underlying malignancy is not common following LT. Due to the small number of patients who had relapse of malignancy, it is not possible to determine the factors associated with this complication.
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Four (4.5%) of the patients in this analysis were documented to have new malignancy, and three of them died secondary to complications from the cancer during the follow-up period (0–168 months following LT). The reported deaths from malignancies steadily increase with longer time from LT, accounting for 11%, 15%, and 16% of deaths 3–5 yr, 5–10 yr, and after 10 yr following transplant, respectively (31). These malignancies are primarily skin and lymphoma. Based on this analysis of cases reported in the literature, it does not appear that the HSCT recipients who undergo LT are at a higher risk of developing secondary malignancy. However, it is noteworthy that the two patients from our institution who underwent LT died from new metastatic solid malignancy. This raises the possibility that there is reporting bias with under reporting of patients who developed new malignancy or had relapse of original cancer. Also the small number of patients and relatively short follow-up period may underestimate the risk of malignancy observed in this case series analysis. A prospective, long-term, multicenter registry of cases of LT following HSCT is needed to determine the risk of new or recurrent malignancy in this patient population. Another concern about LT following HSCT is the increased risk of infectious complications. This increased risk is probably related to interruption of mucosal barriers associated with GVHD, hypogammaglobulinemia, prolonged immunosuppressive therapy, and colonization by resistant bacteria such pseudomonas and fungi including aspergillus. While our series does not provide details about the infectious complications during the post-LT course, we do have data on the cause of death following LT and infection was documented as the primary cause of death in seven patients. This represents 8% of all patients and 29% of those who died during the follow-up period. These infections were primarily related to fungi, CMV, and sepsis. Infection is reported as the cause of death in 13– 18% of allogeneic HSCT recipients and 7% following autologous HSCT (32). In the registry of the ISHLT, infections were the cause of death in 38.4%, 23.9%, and 19.9% of those who died 31 d– 1 yr, 1–3 yr, and 3–5 yr following LT, respectively (31). It appears that rate of fatal infections in HSCT recipients who underwent LT is not higher than the general population of LT recipients. The indication for LT in this report was BOS either alone or associated with pulmonary fibrosis in 81% of patients. It is also known that the most important limitations to long-term survival following LT is BOS, which is normally affecting 30–50% of patients (33). So, a major concern is the
Lung transplantation following HSCT recurrence of BOS following LT. In this analysis, BOS was documented in 32.5% of patients who underwent LT following HSCT. So, it appears that the incidence of BOS is not higher than that for other LT recipients. Further prospective studies are needed to determine the exact incidence and natural history of BOS in this patient population. Sixteen patients (19.1%) underwent living donor lobar LT. Most of these patients were in pediatric age and were reported from Japan. Those reports suggest that this is an option for critically ill patients who cannot wait for cadaveric LT (17, 34). Some of these patients received the lobar LT from the same donor who provided the stem cells for the patient. In one report that was not included in our analysis because there were incomplete data and several of the patients were reported in other publications, 19 HSCT recipients received living donor lobar LT. In eight of these patients, one of the donors was the same donor for HSCT. The five-yr survival was significantly higher in the same donor compared to nonsame donor groups. The same donor patients received less immunosuppression and that was associated with less opportunistic infections and less malignancy (34). Also the authors of that report suggested that the HLA mismatch and LT rejection were less frequent in the same donor group and that may reflect on better survival. The findings of the above report need to be validated by multicenter studies. In our analysis, there was no difference in mortality between recipients of living donor lobar LT (25%—four of 16 patients) compared with those who underwent cadaveric LT (29%—20 of 68 patients; HR 0.59 (CI 0.22– 1.60, p = 0.295). Survival rates for LT performed between 2001 and 2012 based on ISHLT Transplant Registry Quarterly Reports for Lung in North America revealed that the unadjusted benchmark survival rate was 88% at three months, 79% at one yr, 64% at three yr, and 53% at five yr (31). In an analysis of data from the United Network for Organ Sharing registry for 15 642 adult patients undergoing lung transplantation between 1987 and 2009 in 61 US transplantation centers, the one-yr, three-yr, and five-yr survival rates were 79.7% (95% CI, 79.1% to 80.4%), 63.0% (95% CI, 62.2% to 63.8%), and 49.5% (95% CI, 48.6% to 50.5%), respectively (35). Patients receiving LT following HSCT in this study had a survival rate of 73% after a median of 36 months follow-up. The probability of survival at two yr and three yr following LT was 0.88 (95% CI 0.78–0.93) and 0.79 (95% CI 0.67–0.87), respectively. There were not enough patients to determine the probability of
survival at five yr in this patient population. Nevertheless, the survival of patients in our report appears to be not inferior to that for general LT recipients. It is possible that the generally younger age of patients who undergo LT following HSCT, the highly selective process and reputable, experienced centers where these procedures are performed play a role in the better survival. It is also important to note that this remains to be a small number of patients and this survival is not compared to a matched group of LT recipients. In a report of 13 LT recipients following HSCT, the one yr (90%) and five yr (75%) survival did not differ from a matched LT controls (85% and 68%, respectively) (26). Further prospective controlled studies are needed to determine the survival of HSCT who undergo LT. Limitations to this study include the retrospective nature of the analysis, the lack of consistency in definitions between the different reports. Also, there is no uniform method of evaluation and decision to proceed with LT among the different reports. The findings in this study lack comparison to a matched control group of LT recipients who did not have HSCT. It is also not possible to determine whether LT provides survival advantage compared with HSCT who have BOS and did not undergo LT. There is also a potential for publication bias and under-reporting as patients with bad outcome following LT may not have been reported. In our Cox regression analysis, only gender was borderline significant; hence, we could not create a model to assess for confounders as all the other variables were not significant. There might be other confounding variables that could help explain this difference that was not reported in the individual cases studies, such as other comorbid conditions. In summary, this large multicenter case series suggests that the overall clinical course and survival of HSCT recipients who undergo LT is comparable with the general population of LT recipients. LT is a reasonable approach for highly selected patients with severe chronic lung disease following HSCT, and this option should be explored with these patients. References 1. GOOLEY TA, CHIEN JW, PERGAM SA et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010: 363: 2091. 2. CHI AK, SOUBANI AO, WHITE AC, MILLER KB. An update on pulmonary complications of hematopoietic stem cell transplantation. Chest 2013: 144: 1913. 3. SOUBANI AO, PANDYA CM. The spectrum of noninfectious pulmonary complications following hematopoietic stem
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Clin Transplant 2014: 28: 776–782 DOI: 10.1111/ctr.12378
Clinical Transplantation
Lung transplantation following hematopoietic stem cell transplantation: report of two cases and systematic review of literature Soubani AO, Kingah P, Alshabani K, Muma G, Haq A. Lung transplantation following hematopoietic stem cell transplantation: report of two cases and systematic review of literature.
Ayman O. Soubania, Pascal Kingaha, Khaled Alshabania, Gilbert Mumab and Athar Haqa a
Abstract: Background: Non-infectious pulmonary complications following hematopoietic stem cell transplantation (HSCT) are major cause of morbidity and mortality with limited treatment options. Lung transplantation (LT) has been rarely reported as a treatment option for selected HSCT recipients with these problems. Objective: Describe the outcome of HSCT recipients who underwent LT. Methods: Two cases of LT following HSCT from our institution are presented. Cases reported in literature were identified using English language PubMed/MEDLINE with keywords hematopoietic stem cell transplantation, bone marrow transplantation, or bronchiolitis obliterans cross-referenced with lung transplantation. We extracted data on baseline characteristics and survival data following LT. Results: Total of 84 patients are analyzed. Age at time of LT was median of 22 yr (range 1–66). Seventy-nine patients were recipients of allogeneic HSCT. The indications for LT were bronchiolitis obliterans syndrome (BOS; 63 patients), pulmonary fibrosis (13 patients), BOS/pulmonary fibrosis (five patients), and graft-versus-host-disease (GVHD) of lung (three patients). The median time between HSCT and LT was 52.3 months (range 6–240). The median follow-up after LT was 36 months (range 0–168). During this time, BOS was documented in 25 patients. Relapse of hematological malignancy was reported in two patients, and new malignancy developed in four patients. At the end of follow-up, 60 patients were alive and 24 patients died. The probability of survival following LT at 24 and 36 months was 0.88 (95% CI 0.78–0.93) and 0.79 (95% CI 0.67–0.87), respectively. Conclusion: LT is a potential therapeutic option in selected patients with severe chronic pulmonary disease following HSCT. Further studies are needed to determine the appropriate timing and the outcome of this approach.
Hematopoietic stem cell transplantation (HSCT) is an important treatment for a variety of neoplastic, hematologic, and genetic conditions. The overall survival of HSCT recipients has been steadily improving (1). Pulmonary complications continue to be a major cause of morbidity and mortality in HSCT recipients (2). The recent advances in the diagnosis and management of infectious and early non-infectious pulmonary complications of HSCT increased the importance of late non-infectious conditions. These late complications are primarily represented by bronchiolitis obliterans syndrome
776
Division of Pulmonary, Critical Care and Sleep Medicine, Karmanos Cancer Center, School of Medicine, Wayne State University, Detroit, MI, and bAstellas Pharma Inc, Chicago, IL, USA
Key words: bronchiolitis obliterans – hematopoietic stem cell transplantation – lung transplantation – outcome – survival Corresponding author: Ayman O. Soubani, MD, Division of Pulmonary, Critical Care and Sleep Medicine, School of Medicine, Wayne State University, 3990 John R-3 Hudson, Detroit, MI 48201, USA. Tel.: 313-966-0695; fax: 313-993-0562; e-mail: [email protected] Conflict of interest: None. Accepted for publication 21 April 2014
(BOS) and to a lesser degree pulmonary fibrosis and bronchiolitis obliterans organizing pneumonia (BOOP) (3). The reported prevalence of BOS following HSCT ranges between 2–5% and up to 14% in long-term survivors with chronic graft-versus-host-disease (GVHD) (4, 5). The mortality associated with BOS following HSCT reaches 60% (6). Medical management of BOS has been frustrating with limited success in stabilizing or reversing the progression of the disease (7). There is increasing number of reports about lung transplantation (LT) as a therapeutic option in selected
Lung transplantation following HSCT patients with BOS following HSCT. However, these reports are primarily based on single case or small case series. Furthermore, there is controversy about the optimal timing for LT, risk of relapse of underlying malignancy, and the survival of these patients following LT. In this report, we describe the clinical course of two HSCT recipients who underwent LT, then systematically review the literature to address these points. Methods
The objective of this study was to address three issues related to LT following HSCT. The first is what is the median time from HSCT to LT reported in the literature. The second issue is the survival of HSCT patients who underwent LT. The third is related to recurrence of underlying cancer or a secondary malignancy following LT in this patient population. For this purpose, we first report two patients from our institution who had allogeneic HSCT and later on underwent LT. Then, we searched the literature using PubMed/ MEDLINE with the keywords or text words “hematopoietic stem cell transplantation,” “bone marrow transplantation or bronchiolitis obliterans cross-referenced with lung transplantation.” We included only reports that were in English language and included adequate clinical details about the patients. Bibliography of these reports was also searched for additional cases. Every effort was made to make sure there were no duplications in the reporting of cases. The data extracted from these references included the age, gender, underlying illness, type of HSCT, the presence of GVHD, diagnosis of lung disease following HSCT, duration between HSCT and LT, type of LT, the presence of BOS following LT, recurrence of underlying disease prior to HSCT, or development of new malignancy. Also, we collected data on the outcome of these patients including the duration of survival following LT and from the original HSCT. These data were tabulated and analyzed. Institutional review board (IRB) approval was obtained to report the two cases. We used chi-square test to compare baseline characteristics for categorical variables and the ttest to compare baseline characteristics for continuous variables. Kaplan–Meier survival estimates were obtained and compared between some baseline characteristics. Log-rank test was used to determine statistical significance. Cox regression analysis was used to determine hazard ratios. Univariate analysis was performed initially, and modeling was considered if statistically significant differences were encountered. p-values of 18 yr) Gender (female vs. male) Duration between HSCT and LT (≤60 vs. >60 months) Type of HSCT (allogeneic vs. autologous) Type of LT (bilateral vs. single/lobar) Underlying lung disease prior to LT (BOS vs. fibrosis) Type of LT donor (cadaveric vs. live donor)
0.60 (0.27–1.37) 0.42 (0.17–1.0) 0.46 (0.19–1.0)
0.23 0.048 0.065
0.66 (0.19–3.83)
0.857
1.4 (0.56–3.6) 1.06 (0.53–2.15)
0.463 0.855
0.59 (0.22–1.60)
0.295
BOS, bronchiolitis obliterans syndrome; HSCT, hematopoietic stem cell transplantation; LT, lung transplantation.
Fig. 1). There was no significant difference in outcome between those patients who underwent bilateral vs. single/lobar LT (HR 1.4 [0.56 3.6, p = 0.463] Fig. 2). When comparing the outcome of patients who underwent LT before vs. after 60 months of HSCT, there was no significant difference in outcome between both groups (HR 0.46 [CI 0.19–1.00, p = 0.065]; Fig. 3). The causes of death were respiratory failure not otherwise specified (four patients), respiratory failure due to BOS or rejection (five patients), fungal infection (three patients—two specified as aspergillosis), CMV encephalitis (two patients), secondary malignancy (three patients, one with metastatic myoepithelial carcinoma of the mandible 104 months following LT, the second with esophageal cancer 30 months following LT, and the third with myxofibrosarcoma 24 months following LT), relapse of underlying hematologic malignancy (two patients—one patient with acute myeloid leukemia (AML) 13 months after LT, and the second patient with
Fig. 2. Cumulative probability of survival from time of lung transplant to end of study compared between single lung transplant and bilateral lung transplant recipients. There was no significant difference in outcome between the two groups during the reported follow-up period (p = 0.463).
Fig. 3. Cumulative probability of survival from time of lung transplant to end of study compared by duration between hematopoietic stem cell transplantation and lung transplantation of less than or more than 60 months (data available on 81 patients). There was no significant difference in outcome between the two groups during the reported follow-up period (p = 0.065).
myelodysplastic syndrome around 10 months following LT). Other causes of death included respiratory syncytial virus (RSV) pneumonia, septicemia, sepsis, multi-organ system failure, and pulmonary hemorrhage following lung biopsy (one patient each). One patient developed EBV-associated post-transplant lymphoproliferative disorder (PTLPD) that was successfully treated with involved field radiation and interferon therapy. The patient was alive five yr after LT. Discussion Fig. 1. Cumulative probability of survival from time of lung transplant to end of study compared between males and females. Females had better outcome during the follow-up period (p = 0.048).
This systematic review of the literature finds that LT was performed on 84 patients who underwent HSCT for a variety of malignancies. A total of 94% of these patients had allogeneic HSCT. The
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indication for LT was primarily BOS. A total of 76% of the patients had bilateral LT, and the majority were from cadaveric donor (81%). The LT were performed a median of 52.3 months following HSCT, and the patients were followed up a median of 36 months following LT. During this time, 2.5% of patients had relapse of underlying malignancy, 4.5% developed a new malignancy, and 28.6% of patients died. There were no significant predictors of survival during the follow-up period. One of the main controversies about performing LT following HSCT is the best timing of LT and risk of relapse of the underlying malignancy. The International Society for Heart and Lung Transplantation (ISHLT) recommends that LT should not be performed in the first two years after HSCT for malignant disease, and it is advisable to have five-yr disease-free interval prior to LT (29). In our analysis, the median time for LT was 52.3 months (range 6–240) following HSCT. When comparing the outcome of patients who underwent LT before vs. after 60 months of HSCT, there was no significant difference in outcome between both groups (HR 0.46 (CI 0.19–1.00, p = 0.065). Our analysis suggests that LT can be performed earlier than five yr following HSCT in selected patients and the overall outcome is not inferior to those who had the LT after five yr from HSCT. Relapse of underlying malignancy is a major concern following HSCT. The reported relapse rate following allogeneic HSCT in general has been in the range of 34–41% (30). This has been a major concern about performing LT in HSCT recipients. In our analysis, only two patients (2.4%) had relapse of the underlying hematologic malignancy during the follow-up period after LT. One patient had relapse of AML and the second relapse of myelodysplastic syndrome (MDS) 13 months and 10 months following LT, respectively. Similar findings were found in a study of 40 HSCT recipients who underwent a variety of solid organ transplants, only 4% had relapse of the underlying malignancy at five yr (23). It is possible that the presence of chronic GVHD in patients with history of HSCT has a protective role against relapse of underlying malignancy by exerting graft vs. leukemia effect. On the other hand, intensifying the immunosuppression following LT may increase the chances of malignancy relapse, especially with aggressive types of acute leukemia. The findings in this study suggest that relapse of underlying malignancy is not common following LT. Due to the small number of patients who had relapse of malignancy, it is not possible to determine the factors associated with this complication.
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Four (4.5%) of the patients in this analysis were documented to have new malignancy, and three of them died secondary to complications from the cancer during the follow-up period (0–168 months following LT). The reported deaths from malignancies steadily increase with longer time from LT, accounting for 11%, 15%, and 16% of deaths 3–5 yr, 5–10 yr, and after 10 yr following transplant, respectively (31). These malignancies are primarily skin and lymphoma. Based on this analysis of cases reported in the literature, it does not appear that the HSCT recipients who undergo LT are at a higher risk of developing secondary malignancy. However, it is noteworthy that the two patients from our institution who underwent LT died from new metastatic solid malignancy. This raises the possibility that there is reporting bias with under reporting of patients who developed new malignancy or had relapse of original cancer. Also the small number of patients and relatively short follow-up period may underestimate the risk of malignancy observed in this case series analysis. A prospective, long-term, multicenter registry of cases of LT following HSCT is needed to determine the risk of new or recurrent malignancy in this patient population. Another concern about LT following HSCT is the increased risk of infectious complications. This increased risk is probably related to interruption of mucosal barriers associated with GVHD, hypogammaglobulinemia, prolonged immunosuppressive therapy, and colonization by resistant bacteria such pseudomonas and fungi including aspergillus. While our series does not provide details about the infectious complications during the post-LT course, we do have data on the cause of death following LT and infection was documented as the primary cause of death in seven patients. This represents 8% of all patients and 29% of those who died during the follow-up period. These infections were primarily related to fungi, CMV, and sepsis. Infection is reported as the cause of death in 13– 18% of allogeneic HSCT recipients and 7% following autologous HSCT (32). In the registry of the ISHLT, infections were the cause of death in 38.4%, 23.9%, and 19.9% of those who died 31 d– 1 yr, 1–3 yr, and 3–5 yr following LT, respectively (31). It appears that rate of fatal infections in HSCT recipients who underwent LT is not higher than the general population of LT recipients. The indication for LT in this report was BOS either alone or associated with pulmonary fibrosis in 81% of patients. It is also known that the most important limitations to long-term survival following LT is BOS, which is normally affecting 30–50% of patients (33). So, a major concern is the
Lung transplantation following HSCT recurrence of BOS following LT. In this analysis, BOS was documented in 32.5% of patients who underwent LT following HSCT. So, it appears that the incidence of BOS is not higher than that for other LT recipients. Further prospective studies are needed to determine the exact incidence and natural history of BOS in this patient population. Sixteen patients (19.1%) underwent living donor lobar LT. Most of these patients were in pediatric age and were reported from Japan. Those reports suggest that this is an option for critically ill patients who cannot wait for cadaveric LT (17, 34). Some of these patients received the lobar LT from the same donor who provided the stem cells for the patient. In one report that was not included in our analysis because there were incomplete data and several of the patients were reported in other publications, 19 HSCT recipients received living donor lobar LT. In eight of these patients, one of the donors was the same donor for HSCT. The five-yr survival was significantly higher in the same donor compared to nonsame donor groups. The same donor patients received less immunosuppression and that was associated with less opportunistic infections and less malignancy (34). Also the authors of that report suggested that the HLA mismatch and LT rejection were less frequent in the same donor group and that may reflect on better survival. The findings of the above report need to be validated by multicenter studies. In our analysis, there was no difference in mortality between recipients of living donor lobar LT (25%—four of 16 patients) compared with those who underwent cadaveric LT (29%—20 of 68 patients; HR 0.59 (CI 0.22– 1.60, p = 0.295). Survival rates for LT performed between 2001 and 2012 based on ISHLT Transplant Registry Quarterly Reports for Lung in North America revealed that the unadjusted benchmark survival rate was 88% at three months, 79% at one yr, 64% at three yr, and 53% at five yr (31). In an analysis of data from the United Network for Organ Sharing registry for 15 642 adult patients undergoing lung transplantation between 1987 and 2009 in 61 US transplantation centers, the one-yr, three-yr, and five-yr survival rates were 79.7% (95% CI, 79.1% to 80.4%), 63.0% (95% CI, 62.2% to 63.8%), and 49.5% (95% CI, 48.6% to 50.5%), respectively (35). Patients receiving LT following HSCT in this study had a survival rate of 73% after a median of 36 months follow-up. The probability of survival at two yr and three yr following LT was 0.88 (95% CI 0.78–0.93) and 0.79 (95% CI 0.67–0.87), respectively. There were not enough patients to determine the probability of
survival at five yr in this patient population. Nevertheless, the survival of patients in our report appears to be not inferior to that for general LT recipients. It is possible that the generally younger age of patients who undergo LT following HSCT, the highly selective process and reputable, experienced centers where these procedures are performed play a role in the better survival. It is also important to note that this remains to be a small number of patients and this survival is not compared to a matched group of LT recipients. In a report of 13 LT recipients following HSCT, the one yr (90%) and five yr (75%) survival did not differ from a matched LT controls (85% and 68%, respectively) (26). Further prospective controlled studies are needed to determine the survival of HSCT who undergo LT. Limitations to this study include the retrospective nature of the analysis, the lack of consistency in definitions between the different reports. Also, there is no uniform method of evaluation and decision to proceed with LT among the different reports. The findings in this study lack comparison to a matched control group of LT recipients who did not have HSCT. It is also not possible to determine whether LT provides survival advantage compared with HSCT who have BOS and did not undergo LT. There is also a potential for publication bias and under-reporting as patients with bad outcome following LT may not have been reported. In our Cox regression analysis, only gender was borderline significant; hence, we could not create a model to assess for confounders as all the other variables were not significant. There might be other confounding variables that could help explain this difference that was not reported in the individual cases studies, such as other comorbid conditions. In summary, this large multicenter case series suggests that the overall clinical course and survival of HSCT recipients who undergo LT is comparable with the general population of LT recipients. LT is a reasonable approach for highly selected patients with severe chronic lung disease following HSCT, and this option should be explored with these patients. References 1. GOOLEY TA, CHIEN JW, PERGAM SA et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010: 363: 2091. 2. CHI AK, SOUBANI AO, WHITE AC, MILLER KB. An update on pulmonary complications of hematopoietic stem cell transplantation. Chest 2013: 144: 1913. 3. SOUBANI AO, PANDYA CM. The spectrum of noninfectious pulmonary complications following hematopoietic stem
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