European Journal of Haematology 92 (459–466)
REVIEW ARTICLE
Acute myeloid leukemia following solid organ transplantation: entity or novelty? Armin Rashidi1, Stephen I. Fisher2 1
Division of Oncology, Washington University School of Medicine, St. Louis, MO; 2Pathology Sciences Medical Group/Sentara Laboratory Services, Norfolk, VA, USA
Abstract Due to the rarity of the disease, the characteristics of acute myeloid leukemia following solid organ transplantation (post-transplant AML; PT-AML) are unclear; furthermore, it is not known for certain whether PT-AML is a separate entity or not. We provide a systematic review of all previously reported cases of PT-AML in the English literature (n = 51). 45% of cases occurred after renal transplantation, and 72% were males. The median age at diagnosis of AML was 50 yr, with a median transplant-to-AML interval of 3.8 yr and a rapid decline in incidence after 5 yr. 26% of patients were asymptomatic at the time of presentation, and 42% were pancytopenic. M0/M1/M2, M3, M4/M5, and M6/M7 subtypes comprised 17%, 25%, 39%, and 19% of all cases, respectively. 36% of patients had unfavorable cytogenetic risk disease. The median overall survival was only 3 months. We observed several transplantspecific features: (i) The transplant-to-AML interval follows two very different patterns between renal vs. liver transplant patients. (ii) All 4 cases of donor cell leukemia occurred after liver transplant. (iii) Unfavorable risk disease was marginally significantly more common among renal compared with liver transplant patients (P = 0.057). Our results suggest that PT-AML is a separate entity with distinct characteristics, which need to be investigated further in future research. Heavy post-transplant immunosuppression likely plays a key role in the pathogenesis of PT-AML. Key words leukemia; myeloid; solid; transplantation Correspondence Armin Rashidi, MD, PhD, Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO 63110, USA. Tel: +314 747 8479; Fax: +314 362 7086; e-mail: [email protected] Accepted for publication 4 February 2014
Iatrogenic immunosuppression after solid organ transplantation is associated with an increased risk of malignancy, with an average overall prevalence of 6% increasing to a prevalence of 40% 20 yr after transplantation. The most common of such malignancies are skin cancer and lymphoma, comprising up to 80% of all cases (1). In the Cincinnati Transplant Tumor Registry study performed in 1991, leukemia accounted for 2.7% of non-cutaneous tumors, with acute myeloid leukemia (AML) making up 43% of these. The interval between transplantation and AML ranged from 4.5 to 287 months, with an average of 85 months (2). The complete remission rate was 56% with intensive chemotherapy in a previous study (3). It is believed that there is no predominance of a specific FAB subtype in post-transplantation AML (3). Due to the remarkable rarity of post-transplant AML (PT-AML), our understanding of this condition stems
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12288
mainly from sporadic case reports. We define PT-AML as acute myeloid leukemia that (i) develops after solid organ transplantation and (ii) is not preceded by myelodysplastic syndromes or myeloproliferative disorders, in a patient without a prior history of radiation therapy, chemotherapy, or de novo AML. Data for this review were identified by searches of MEDLINE, PubMed, and references from relevant articles using a combination of ‘acute leukemia’ and one of the following search terms: ‘solid organ’, ‘renal transplant’, ‘kidney transplant’, ‘renal allograft’, ‘liver transplant’, ‘lung transplant’, ‘heart transplant’, ‘cardiac transplant’, ‘bowel transplant’, and ‘pancreas transplant’. Only articles published in English until December 1, 2013 and with available full-text were included. To the best of our ability, we avoided duplicates, which could have occurred in the previous literature as a
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result of cross-citations. A total of 51 eligible cases were found and analyzed (Table S1; Online Resource). In this article, we frequently use the two largest previous studies for comparison purposes. The first study included 4455 solid organ transplant recipients (kidney: 4184; heart: 185; liver: 65; pancreas: 13; combined heart/lung: 5; upper abdominal organ ‘cluster’: 2; lung: 1) (2). The second study was a case report and a review of the previously reported 48 cases of PT-AML (kidney: 24, liver: 18, heart: 5, lung: 1) (4). For statistical analysis, we used the Statistical Package for the Social Sciences (SPSS, version 21.0, Chicago, IL, USA) and Microsoft Excel 2010. Given the fairly sample size and skewed distributions, median (interquartile range; IQR) was used to describe central tendency. Proportions were compared using the chi-square test and the Fisher’s exact test. The Mann– Whitney’s U-test and the Kruskal–Wallis tests were used to compare means between independent groups (two or more than two, respectively). Kaplan–Meier curves with Cox regression were constructed for survival analysis. Throughout analysis, P < 0.05 was considered statistically significant. Does PT-AML exist?
The incidence of AML following solid organ transplantation was estimated in a study performed in 1993 to be the same as the incidence seen in the general population (2). This estimation raises the natural question of whether PT-AML is a separate entity from non-PT-AML, or, are post-transplant patients and other individuals affected equally frequently by AML? The presence of one or more of the following characteristic features would argue that PT-AML is truly a separate entity: (i) if laboratory or pathological features of AML (e.g., predilection for a rare or unusual AML subtype, idiosyncratic immunophenotypic, molecular, or cytogenetic findings) are different in post-transplant cases from those in other affected individuals, (ii) if demographics of AML following solid organ transplantation (after accounting for baseline differences between demographics of transplant patients in general and the general population) are different from de novo AML, (iii) if the incidence/prevalence of AML following solid organ transplantation depends on the specific organ transplanted or the specific immunosuppressive therapy, and (iv) if the interval between transplantation and AML following solid organ transplantation depends on the specific organ transplanted or the specific immunosuppressive therapy. While determination of these specific features for a rare disease is difficult, we attempt, in the subsequent sections of this article, to evaluate and answer the critical question: Does PT-AML exist? Demographics and clinical presentation
Two cases of AML were encountered among 1552 liver transplant recipients in a Korean institution, suggesting an
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incidence of approximately 0.13% (5). This rate was estimated to be 3/799 (0.38%) (6), 1/764 (0.13%) (7), 2/1365 (0.15%) (8), and 2/1140 (0.18%) (9) among liver transplant recipients in other studies. Among 876 patients that underwent renal transplantation in the University of Cincinnati Medical School, one (0.1%) developed AML (10). This incidence was estimated to be 2/969 (0.2%) (11) and 2/1884 (0.1%) (12) in other large series. Among 631 patients that had a heart transplantation in a German study, three (0.5%) patients developed AML (13). This rate was 1/124 (0.8%) in an older study carried out in Stanford (14). Although the overall incidence of PT-AML remains very low, large epidemiological studies have demonstrated a significantly increased risk of AML in the post-transplant population when compared with the general population. Camos et al. (6) showed that the incidence of AML following liver transplantation is higher than expected for the general population. Similarly, Offman et al. (15) showed, in a large population study of more than 170 000 organ recipients, that organ transplantation was associated with an increased risk of AML. Specifically, the relative risk of AML in transplant recipients compared with controls matched for age, sex, and geographical origin was 5.5 for heart/lung and 2.1 for kidney recipients. 90% and 64% of heart/lung and kidney recipients, respectively, who developed PT-AML were males. The sex bias, as the authors mentioned, might have arisen from the predominance of males among transplant recipients. In the largest multicentric study to date (16), reviewing data from more than 200 000 cases of renal and 30 000 cases of heart transplantation, the standardized incidence ratios for developing AML were 1.9 and 5.1, respectively (P < 0.001 for both). Offman et al. (15) noted that while there is an excess of AML (compared with the general population) in the first 3– 4 yr after transplantation, the incidence of PT-AML diverged sharply from the expected incidence thereafter. In a comparative analysis of patients with postrenal transplantation AML (n = 16) and postliver transplantation AML (n = 13), the median interval between transplantation and AML was significantly longer for the former patients (5.5 vs. 2 yr, respectively; P = 0.03) (5). Twelve (3.4%) of the 348 patients in another large study of postrenal transplantation developed AML (17), with a latency interval of at least 11 months, and 100% disease-related mortality. In a large previous study, the increased risk of AML after heart transplantation did not begin until 3–4 yr post-transplant, whereas the risk of AML after renal transplantation started to rise earlier and in a linear manner (16). The reported cases of PT-AML in our series increased in frequency from 1974 (first case) to 2000, when the incidence peaked, and then declined again until 2013 (Fig. 1). With the rarity of PT-AML and potential publication bias, it is hard to determine whether the apparent peak around year 2000 represents a true increase in incidence. Cases from
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Figure 1 Demographics of PT-AML. The reported cases of PT-AML increased in frequency from 1974 (first case) to 2000, when the incidence peaked, and then declined again to 2013. Cases from North America and Europe comprised 84% of the entire data set (n = 50).
North America (44%) and Europe (40%) comprised 84% of the entire data set (Fig. 1; n = 50). Again, publication bias may explain this difference in incidence among continents. Table 1 shows a summary of our analysis. PT-AML occurred after transplantation of kidneys, liver, heart, and lungs in 23 (45%), 20 (39%), 6 (12%), and 2 (4%) cases, respectively. The nature of the present review does not allow for comparing different organ transplantation categories in terms of PT-AML incidence. The median age at diagnosis of AML was 50 yr, 5 yr older than a previous large report (4). The median age at diagnosis of AML increased significantly from kidney to liver to heart to lung recipients (P = 0.023). The simplest explanation for this trend is the presence of a similar trend for age at transplantation (P = 0.039). Similar
to a large previous report (4), the majority (72%) of our cases were males, again probably reflecting the typical transplant population. The median transplant-to-AML interval was 3.8 yr (similar to a large previous study reporting an estimate of 4 yr (4)) and was not different among recipients of different organ transplants (P = 0.09). More than 70% of cases of PT-AML occurred within 5 yr of organ transplantation; the incidence rapidly declined following this early-post-transplant critical period (Fig. 2, inset). Limiting the analysis to the two most common categories (renal and liver transplantations) revealed a significantly longer median transplant-toAML interval with kidney compared with liver transplant recipients (P = 0.046). The majority of cases of PT-AML after renal transplantation occurred within the first 5 yr, and the incidence rapidly diminished thereafter to make a long tail extending to up to two decades after the transplant. After liver transplantation, on the other hand, no such peak-andtail pattern was observed; all cases of PT-AML occurred within the first 8 yr post-transplant (P = 0.024; Fig. 2). There was no correlation between the transplant-to-AML interval and age at diagnosis of AML (P = 0.09). Similarly, there was no association between gender and any of the following variables: age at diagnosis of AML (P = 0.75), transplant-to-AML interval (P = 0.89), and the transplanted organ (P = 1.00). Twenty-five, 21, 3, and 2 patient(s) were receiving 2, 3, 1, and 4 immunosuppressive medications after transplantation, respectively. There was no correlation between the number of immunosuppressive medications and the following variables: age at diagnosis of AML (P = 0.88), transplant-to-AML interval (P = 0.21), and gender (P = 0.09). Not surprisingly, renal and liver transplant patients were exposed to a significantly smaller number of immunosuppressive medications than heart and lung transplant patients (P = 0.005).
Table 1 Comparison between the groups according to the transplanted organ
Age (yr)1 Males (%) Interval (yr)1 No. immunosuppressive medications (1:2:3:4) GC:Tac:MMF:Csp:azathioprine:others Incidental diagnosis (%) WBC at diagnosis of AML (n = 27)1 Pancytopenia (%) M0:M1:M2:M3:M4:M5:M6:M7 Unfavorable risk (%)
All (n = 51)
Kidney (n = 23)
Liver (n = 20)
Heart (n = 6)
Lung (n = 2)
P-value
50 (38–59) 36/50 (72) 3.8 (2.2–6.0) 26:21:2:2 45:15:8:23:27:5 10/39 (26) 7.0 (2.8–49.7) 13/31 (42) 1:3:2:9:10:4:5:2 12/33 (36)
41 (37–52) 16 (70) 4.7 (2.5–7.4) 1:12:10:0 22:1:3:9:18:2 8/19 (42) 8.9 (3–46.3) 6/15 (40) 0:1:1:3:5:1:3:0 8/14 (57)
50 (37–61) 14 (70) 3.0 (1.7–4.0) 2:13:4:1 15:13:4:7:3:1 2/14 (14) 4.4 (2.1–25.0) 5/12 (42) 1:1:1:6:4:1:0:1 3/16 (19)
58 (52–61) 4/5 (80) 4.2 (3.8–6.1) 0:0:5:1 6:0:1:6:4:2 0/4 (0) 137 (n = 1) 0/1 (0) 0:1:0:0:1:1:1:1 1/3 (33)
61 (57–61) 2 (100) 2.9 (0.8–2.9) 0:0:2:0 2:1:0:1:2:0 0/2 (0) 6.3 (n = 1) 1/2 (50) 0:0:0:0:0:1:1:0 –
0.023* 1.00 0.09 0.005** – 0.20 0.51 1.0 – 0.10
GC, glucocorticoids; Tac, tacrolimus; MMF, mycophenolate mofetil; Csp, cyclosporine. Median (interquartile range). *P < 0.05. **P < 0.01. –: too few cases to analyze.
1
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Figure 2 Transplant-to-AML interval. The median transplant-to-AML interval was 3.8 yr. More than 70% of cases of PT-AML occurred within 5 yr of organ transplantation; the incidence rapidly declined following this early-post-transplant critical period. The majority of cases of PT-AML after renal transplantation occurred within the first 5 yr, and the incidence rapidly diminished thereafter to make a long tail extending to up to two decades after the transplant. After liver transplantation, on the other hand, no such peak-and-tail pattern was observed; all cases of PT-AML occurred within the first 8 yr posttransplant.
The diagnosis of PT-AML was suspected based on incidentally observed abnormalities on complete blood count in 26% of patients. Incidental diagnosis did not have an association with the transplanted organ (P = 0.20), gender (P = 0.43), age at diagnosis of AML (P = 0.92), and transplant-to-AML interval (P = 0.65). Two of 39 patients (5.1%) presented with extramedullary disease. Pathogenesis and laboratory findings
It is reasonable to assume that diminished immune surveillance, the main mechanism responsible for post-transplant malignancies in general, could also increase the risk of development of acute leukemia (18). Chronic acceptance of the allograft reflects the iatrogenic paralysis of the immune system and the potential for leukemia emergence. Other potential mechanisms include direct mutagenic effects of immunosuppressive medications, opportunistic infections with oncogenic viruses, and chronic antigenic stimulation by the transplanted organ (19). The frequency of PT-AML was significantly correlated with the dose of azathioprine at 1 yr after transplantation in a large study by Offman et al. (15). They suggested that the ability of azathioprine to promote clonal expansion of DNA mismatch repair (MMR)-deficient myeloid cells is consistent with the role of post-transplant azathioprine in PT-AML (e.g., selection for the rare MMR-deficient, azathioprineresistant myeloid cells). Clearly, azathioprine effects are not
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the sole mechanism for PT-AML because, for example, only one of the 9 patients with PT-AML in the review of liver transplant recipients by Camos et al. (6) had received azathioprine for immunosuppression. The frequency of using specific immunosuppressive medications in each group in our series is shown in Table 1. The use of azathioprine was associated with a significantly longer median transplant-toAML interval (4.8 [IQR: 3–7.4] vs. 3.1 [IQR: 2–4.2] yr; P = 0.033). No such pattern was observed with other immunosuppressive medications. However, the use of azathioprine was significantly more common among renal compared with liver transplant patients (P < 0.01). In a regression model with transplant-to-AML interval (transformed and normalized) as the dependent variable and transplanted organ (kidney vs. liver), azathioprine use (0 vs. 1), and age at diagnosis of AML as potential predictors, none were significant independent predictors (P = 0.33, 0.24, and 0.60, respectively), suggesting that there is another factor that causes the difference in transplant-to-AML interval between renal and liver transplant cases. Because the two groups were similar in all other studied variables, we are not able, based on these data, to find the root of the difference. Finally, the median number of immunosuppressive medications was not different between groups with renal vs. liver transplants (P = 0.34). The frequency of different FAB subtypes of AML in our series was as follows (n = 36): M0 (3%), M1 (8%), M2 (6%), M3 (25%), M4 (28%), M5 (11%), M6 (14%), M7 (6%). The groups with different transplanted organs were not different in FAB subtype distribution. We then grouped different subtypes as M0/M1/M2, M3, M4/M5, and M6/M7 for more specific analysis. These subgroups were not different in the following variables: gender (P = 0.34), transplantto-AML interval (P = 0.64), transplanted organ (P = 0.58), number of immunosuppressive medications (P = 0.32), incidental diagnosis (P = 0.33), azathioprine use (P = 0.16), and unfavorable risk group (P = 0.39). There was a marginally significant association between the subgroups and age (P = 0.051). The median age at the time of diagnosis of AML increased from 41 (28–54) yr in M3 and 41 (25–58) yr in M4/M5 to 53 (49–64) yr in M0/M1/M2 and 59 (42– 64) yr in M6/M7. According to current WHO 2008 guidelines, the unfavorable risk group included patients with 5/del(5q), 7/del(7q), inv(3q)/t(3;3), abnormalities of 11q, 20q, 21q, del (9q), t(6;9), t(9;22), abnormalities of 17p, or a complex karyotype (3 or more abnormalities) (20). All other patients and patients with inv(16)/t(16;16) with or without any additional abnormalities and with t(8;21) and not part of a complex karyotype were included in the intermediate/favorable risk group. The groups with different transplanted organs were not different in the frequency of unfavorable risk disease (P = 0.10; Table 1). Patients with renal transplant had a marginally significant higher frequency of unfavorable risk
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disease than those with liver transplant (57% vs. 19%, respectively; P = 0.057). There was no association between unfavorable risk disease and any of the following: age at diagnosis of AML (P = 0.34), transplant-to-AML interval (P = 0.45), gender (P = 0.43), incidental diagnosis (P = 0.23), number of immunosuppressive medications used (P = 0.70). Although unfavorable risk disease was not significantly associated with use of any specific immunosuppressive medication, it was more common among patient who used azathioprine than those who did not (57% vs. 21%, P = 0.066). The median WBC count at presentation was not different across groups with different transplanted organs (P = 0.51) and was not associated with any other variable, including age (P = 0.35), gender (P = 0.91), number of immunosuppressive medications (P = 0.27), transplant-to-AML interval (P = 0.90), azathioprine use (P = 0.21), incidental diagnosis (P = 1.0), FAB subtypes (P = 0.07), and unfavorable risk disease (P = 0.69). Not surprisingly, the median WBC count was significantly higher in the M4/M5 subgroup than other subgroups (P = 0.017); this is consistent with the observation in the non-transplant setting that myelomonocytic and monocytic leukemias tend to present with higher WBC counts. A total of 13/31 (42%) patients were pancytopenic at the time of diagnosis of AML. There was no association between pancytopenia at presentation and the following variables: age at diagnosis of AML (P = 0.14), gender (P = 0.69), transplant-to-AML interval (P = 0.27), transplanted organ (P = 0.92), number of immunosuppressive medications (P = 0.28), azathioprine use (P = 0.46), and unfavorable risk disease (P = 0.40). However, pancytopenia was significantly less common among M4/M5 cases than other subgroups (P = 0.007). Finally, leukemia was donorderived in four patients; interestingly, all of these four cases occurred postliver transplantation. Treatment and prognosis
The feasibility of intensive induction chemotherapy is a problem in PT-AML because these patients are typically struggling with their fragile transplanted organ function and an increased treatment-related mortality (21). Although in the majority of reported cases, immunosuppressive medications were decreased or held at the time of diagnosis of AML, this was rarely sufficient. The only exception was a case of postrenal transplantation AML-M4 that went into CR simply with releasing immunosuppression (22). This case clearly demonstrates the role of the immune system in PT-AML and underscores the difficulty in balancing the need for allograft survival with myeloablative leukemic induction chemotherapy. In our series, three patients received allogeneic and one received autologous hematopoietic stem cell transplantation following chemotherapy, four died before receiving treatment,
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and one was treated only by discontinuing the immunosuppressive medications. The treatment was not available in 7 cases. The prognosis was generally poor, with a median overall survival of only 3 (95% confidence interval: 0.8–5.0) months (Fig. 3A). Similar to our series, a large previous report made an estimate of 2.6 months for median overall survival (4). There was no association between overall survival and the following variables: gender (P = 0.27), age (P = 0.34), transplant-to-AML interval (P = 0.29), number of immunosuppressive medications (P = 0.81), use of azathioprine (P = 0.12), pancytopenia at presentation (P = 0.79), and unfavorable risk disease (P = 0.23; Fig. 3B). The lack of a statistically significant effect of unfavorable risk on survival may be due to the very poor prognosis of PT-AML, requiring a substantially larger sample to demonstrate any measurable effect. The FAB subgroup M3 (acute promyelocytic leukemia) had a marginally significant longer survival than non-M3 cases (P = 0.057; Fig. 3C). After excluding cases with lung or heart transplantation, the survival curves were similar between liver and renal transplant groups (P = 0.87; Fig. 3D). Conclusions
About half of our cases occurred after renal transplantation, probably reflecting the commonness of renal transplantation in general. Similarly, more than 70% of our cases were males, probably reflecting the typical transplant population. The median age at diagnosis of AML was 50 yr, with a median transplant-to-AML interval of 3.8 yr. More than 70% of cases of PT-AML occurred within 5 yr of organ transplantation, and the incidence rapidly declined afterward. More than 25% of cases were asymptomatic at the time of presentation, while about 4% presented with myeloid sarcoma. The distribution of different FAB subgroups in our series was as following: M0/M1/M2 (17%), M3 (25%), M4/ M5 (39%), and M6/M7 (19%). Pancytopenia was present in 42% of all patients at presentation. 36% of patients had unfavorable cytogenetic risk disease. The prognosis was generally poor, with an estimated median overall survival of only 3 months. Although the frequency of unfavorable risk disease in our series was similar to the non-transplant-related AML, the prognosis was much poorer (23), suggesting that in addition to cytogenetic category, there are other factors specific to transplant patients that determine their prognosis. As we describe below, the biology of PT-AML may also be different from non-transplant-related AML. Treatment of post-transplant patients is very challenging for several reasons. Pre-existing immunosuppression at the time of diagnosis of AML increases treatment-related mortality. Unfortunately, the release of immunosuppression is not only insufficient for control of AML, but it may also be associated with graft rejection. The latter risk is particularly high in the first few years after the transplant, which is the time period with maximal incidence of PT-AML.
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A
B
C
D
Figure 3 Survival analysis. PT-AML has a poor prognosis, with a median overall survival of only 3 (95% CI: 0.8–5.0) months (A). Although overall survival appeared to be shorter with unfavorable risk disease, the difference did not reach statistical significance (P = 0.23; B). The FAB subgroup M3 (acute promyelocytic leukemia) had a marginally significant longer survival than non-M3 cases (P = 0.057; C). Survival curves were similar between liver and renal transplant groups (P = 0.87; D).
Returning to our original question of whether PT-AML is a distinct entity, our analysis provides compelling evidence in support of this hypothesis. (i) The transplant-to-AML interval follows two very different patterns between renal vs. liver transplant patients. Compared with liver transplant patients, AML following renal transplantation occurs significantly later and continues to occur longer (although at low frequencies) up to two decades after the transplant. The incidence of AML following liver transplantation approaches zero after the first 7 yr post-transplantation. We showed that the more frequent use of azathioprine after renal transplantation was not the cause for this interesting difference between the two groups. (ii) The initially high and later diminishing incidence of PT-AML seems to be associated with more immunosuppression early after trans-
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plantation and tapering of the immunosuppression over time. (iii) Although we had only a few cases of donor cell AML, all four cases occurred in liver transplant patients. Our understanding of the leukemogenic mechanisms in donor cell leukemia is nascent (24), but it appears that the recipient’s bone marrow niche and extrinsic cues influencing the marrow play an important role. Interestingly, not all donors from whom donor cell leukemia develops in the recipient develop leukemia (25), further supporting the hypothesis that recipient-specific factors are at least as important as intrinsic cell processes in donor cell leukemogenesis. (iv) Unfavorable risk disease was marginally significantly more common among renal compared with liver transplant patients and was associated, although not statistically significantly, with the use of azathioprine.
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Can the higher frequency of unfavorable risk disease in renal transplant patients be linked to their longer transplantto-AML interval compared with liver transplant patients? We hypothesize that immune surveillance against AML clones is stronger after renal compared with liver transplantation. As a result, the battle between the subclinical clone(s) and the immune system lasts longer after renal transplantation. Therefore, the AML clone(s) that most effectively evades and eventually defeats the immune system is a more resistant clone(s) and is harder to eradicate and control using conventional treatment approaches, a feature associated with unfavorable risk cytogenetics. In general, one would not expect to see differences in AML features between different organ transplantations if AML following transplantation was not different from AML in the non-transplant setting. Additionally, the standardized incidence ratios for developing AML have been estimated to be significantly higher following renal and heart transplantations than in the general population (1.9 and 5.1, respectively; P < 0.001 for both) (16). Finally, the remarkably skewed time dependence of AML following transplantation (i.e., early peak followed by rapid decline) supports PTAML, a separate entity. This pattern is similar to therapyrelated AML, which is now considered a distinct category in AML classification (26). Although the above findings, as presented, are not intended to offer irrefutable proof that PTAML is a separate entity, they do provide strong evidence that solid organ transplantation is associated with specific patterns in the natural history of AML. Heavy post-transplant immunosuppression likely plays a key role in the pathogenesis of PT-AML. Unfortunately, with the rarity of PTAML, and infeasibility of prospective clinicopathologic studies, future insights into the pathogenesis and management PT-AML are likely to remain obscure. Clearly more research is needed, perhaps in the form of a large multi-institutional collaborative database, to investigate and validate our significant findings and clarify whether some statistically non-significant or marginally significant results were due to a small sample size alone. Conflict of interest and sources of funding
The authors declare that they have no conflict of interest or sources of funding. References 1. Penn I. Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 1993;12:S328–36. 2. Penn I. Cancer in the immunosuppressed organ recipient. Transplant Proc 1991;23:1771–2. 3. Thalhammer-Scherrer R, Wieselthaler G, Knoebl P, et al. Post-transplant acute myeloid leukemia (PT-AML). Leukemia 1999;13:321–6.
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4. Kourelis TV, Boruchov A, Hull D, et al. Acute myeloid leukemia following solid organ transplantation: case report and comprehensive review. Conn Med 2012;76:151–4. 5. Cho YU, Chi HS, Park CJ, et al. Two cases of post-liver transplant acute myeloid leukemia in Korean adults: review of bibliographies and comparison with post-renal transplant acute myeloid leukemia. Ann Hematol 2008;87:513–4. 6. Camos M, Esteve J, Rimola A, et al. Increased incidence of acute myeloid leukemia after liver transplantation? Description of three new cases and review of the literature. Transplantation 2004;77:311–3. 7. Jiang N, Li H, Wang GS, et al. Acute leukemia, a rare but fatal complication after liver transplantation. Leuk Res 2009;33:1349–51. 8. Doti CA, Gondolesi GE, Sheiner PA, et al. Leukemia after liver transplant. Transplantation 2001;72:1643–6. 9. Saigal S, Norris S, Muiesan P, et al. Evidence of differential risk for posttransplantation malignancy based on pretransplantation cause in patients undergoing liver transplantation. Liver Transpl 2002;8:482–7. 10. Barrett WL, First MR, Aron BS, Penn I. Clinical course of malignancies in renal transplant recipients. Cancer 1993;72:2186–9. 11. Krueger TC, Tallent MB Jr, Richie RE, et al. Neoplasia in immunosuppressed renal transplant patients: a 20-year experience. South Med J 1985;78:501–6. 12. Sheil AG. Cancer in renal allograft recipients in Australia and New Zealand. Transplant Proc 1977;9:1133–6. 13. Huebner G, Karthaus M, Pethig K, et al. Myelodysplastic syndrome and acute myelogenous leukemia secondary to heart transplantation. Transplantation 2000;70:688–90. 14. Krikorian JG, Anderson JL, Bieber CP, et al. Malignant neoplasms following cardiac transplantation. JAMA 1978;240:639–43. 15. Offman J, Opelz G, Doehler B, et al. Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation. Blood 2004;104:822–8. 16. Gale RP, Opelz G. Commentary: does immune suppression increase risk of developing acute myeloid leukemia? Leukemia 2012;26:422–3. 17. Ho WK, Robertson MR, Macdonald GJ, et al. Association of acute leukaemia with chlorambucil after renal transplantation. Lancet 1994;343:1298–9. 18. Fahey JL. Cancer in the immunosuppressed patient. Ann Intern Med 1971;75:310–2. 19. Penn I. Development of cancer as a complication of clinical transplantation. Transplant Proc 1977;9:1121–7. 20. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC, 2008. 21. Cuthbert RJ, Russell NH, Jones PA, Morgan AG. Treatment of acute myeloid leukaemia in a renal allograft recipient: implications of cyclosporin immunosuppressive treatment. J Clin Pathol 1991;44:693–5. 22. Dixit MP, Farias KB, McQuade M, Scott KM. Acute myelo-monocytic infiltrate of the lower esophagus in a
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4-year-old renal transplant recipient. Am J Kidney Dis 2003;41:E16. 23. Arellano M, Bernal-Mizrachi L, Pan L, et al. Prognostic significance of leukopenia at the time of diagnosis in acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 2011;11:427– 32. 24. Flynn CM, Kaufman DS. Donor cell leukemia: insight into cancer stem cells and the stem cell niche. Blood 2007;109:2688–92. 25. Hertenstein B, Hambach L, Bacigalupo A, et al. Development of leukemia in donor cells after allogeneic stem cell transplan-
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tation–a survey of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 2005;90:969–75. 26. Bhatia S. Therapy-related myelodysplasia and acute myeloid leukemia. Semin Oncol 2013;40:666–75.
Supporting Information
Additional Supporting Information may be found in the online version of this article: Table S1. Summary of the reported cases of PT-AML.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
REVIEW ARTICLE
Acute myeloid leukemia following solid organ transplantation: entity or novelty? Armin Rashidi1, Stephen I. Fisher2 1
Division of Oncology, Washington University School of Medicine, St. Louis, MO; 2Pathology Sciences Medical Group/Sentara Laboratory Services, Norfolk, VA, USA
Abstract Due to the rarity of the disease, the characteristics of acute myeloid leukemia following solid organ transplantation (post-transplant AML; PT-AML) are unclear; furthermore, it is not known for certain whether PT-AML is a separate entity or not. We provide a systematic review of all previously reported cases of PT-AML in the English literature (n = 51). 45% of cases occurred after renal transplantation, and 72% were males. The median age at diagnosis of AML was 50 yr, with a median transplant-to-AML interval of 3.8 yr and a rapid decline in incidence after 5 yr. 26% of patients were asymptomatic at the time of presentation, and 42% were pancytopenic. M0/M1/M2, M3, M4/M5, and M6/M7 subtypes comprised 17%, 25%, 39%, and 19% of all cases, respectively. 36% of patients had unfavorable cytogenetic risk disease. The median overall survival was only 3 months. We observed several transplantspecific features: (i) The transplant-to-AML interval follows two very different patterns between renal vs. liver transplant patients. (ii) All 4 cases of donor cell leukemia occurred after liver transplant. (iii) Unfavorable risk disease was marginally significantly more common among renal compared with liver transplant patients (P = 0.057). Our results suggest that PT-AML is a separate entity with distinct characteristics, which need to be investigated further in future research. Heavy post-transplant immunosuppression likely plays a key role in the pathogenesis of PT-AML. Key words leukemia; myeloid; solid; transplantation Correspondence Armin Rashidi, MD, PhD, Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO 63110, USA. Tel: +314 747 8479; Fax: +314 362 7086; e-mail: [email protected] Accepted for publication 4 February 2014
Iatrogenic immunosuppression after solid organ transplantation is associated with an increased risk of malignancy, with an average overall prevalence of 6% increasing to a prevalence of 40% 20 yr after transplantation. The most common of such malignancies are skin cancer and lymphoma, comprising up to 80% of all cases (1). In the Cincinnati Transplant Tumor Registry study performed in 1991, leukemia accounted for 2.7% of non-cutaneous tumors, with acute myeloid leukemia (AML) making up 43% of these. The interval between transplantation and AML ranged from 4.5 to 287 months, with an average of 85 months (2). The complete remission rate was 56% with intensive chemotherapy in a previous study (3). It is believed that there is no predominance of a specific FAB subtype in post-transplantation AML (3). Due to the remarkable rarity of post-transplant AML (PT-AML), our understanding of this condition stems
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doi:10.1111/ejh.12288
mainly from sporadic case reports. We define PT-AML as acute myeloid leukemia that (i) develops after solid organ transplantation and (ii) is not preceded by myelodysplastic syndromes or myeloproliferative disorders, in a patient without a prior history of radiation therapy, chemotherapy, or de novo AML. Data for this review were identified by searches of MEDLINE, PubMed, and references from relevant articles using a combination of ‘acute leukemia’ and one of the following search terms: ‘solid organ’, ‘renal transplant’, ‘kidney transplant’, ‘renal allograft’, ‘liver transplant’, ‘lung transplant’, ‘heart transplant’, ‘cardiac transplant’, ‘bowel transplant’, and ‘pancreas transplant’. Only articles published in English until December 1, 2013 and with available full-text were included. To the best of our ability, we avoided duplicates, which could have occurred in the previous literature as a
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result of cross-citations. A total of 51 eligible cases were found and analyzed (Table S1; Online Resource). In this article, we frequently use the two largest previous studies for comparison purposes. The first study included 4455 solid organ transplant recipients (kidney: 4184; heart: 185; liver: 65; pancreas: 13; combined heart/lung: 5; upper abdominal organ ‘cluster’: 2; lung: 1) (2). The second study was a case report and a review of the previously reported 48 cases of PT-AML (kidney: 24, liver: 18, heart: 5, lung: 1) (4). For statistical analysis, we used the Statistical Package for the Social Sciences (SPSS, version 21.0, Chicago, IL, USA) and Microsoft Excel 2010. Given the fairly sample size and skewed distributions, median (interquartile range; IQR) was used to describe central tendency. Proportions were compared using the chi-square test and the Fisher’s exact test. The Mann– Whitney’s U-test and the Kruskal–Wallis tests were used to compare means between independent groups (two or more than two, respectively). Kaplan–Meier curves with Cox regression were constructed for survival analysis. Throughout analysis, P < 0.05 was considered statistically significant. Does PT-AML exist?
The incidence of AML following solid organ transplantation was estimated in a study performed in 1993 to be the same as the incidence seen in the general population (2). This estimation raises the natural question of whether PT-AML is a separate entity from non-PT-AML, or, are post-transplant patients and other individuals affected equally frequently by AML? The presence of one or more of the following characteristic features would argue that PT-AML is truly a separate entity: (i) if laboratory or pathological features of AML (e.g., predilection for a rare or unusual AML subtype, idiosyncratic immunophenotypic, molecular, or cytogenetic findings) are different in post-transplant cases from those in other affected individuals, (ii) if demographics of AML following solid organ transplantation (after accounting for baseline differences between demographics of transplant patients in general and the general population) are different from de novo AML, (iii) if the incidence/prevalence of AML following solid organ transplantation depends on the specific organ transplanted or the specific immunosuppressive therapy, and (iv) if the interval between transplantation and AML following solid organ transplantation depends on the specific organ transplanted or the specific immunosuppressive therapy. While determination of these specific features for a rare disease is difficult, we attempt, in the subsequent sections of this article, to evaluate and answer the critical question: Does PT-AML exist? Demographics and clinical presentation
Two cases of AML were encountered among 1552 liver transplant recipients in a Korean institution, suggesting an
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incidence of approximately 0.13% (5). This rate was estimated to be 3/799 (0.38%) (6), 1/764 (0.13%) (7), 2/1365 (0.15%) (8), and 2/1140 (0.18%) (9) among liver transplant recipients in other studies. Among 876 patients that underwent renal transplantation in the University of Cincinnati Medical School, one (0.1%) developed AML (10). This incidence was estimated to be 2/969 (0.2%) (11) and 2/1884 (0.1%) (12) in other large series. Among 631 patients that had a heart transplantation in a German study, three (0.5%) patients developed AML (13). This rate was 1/124 (0.8%) in an older study carried out in Stanford (14). Although the overall incidence of PT-AML remains very low, large epidemiological studies have demonstrated a significantly increased risk of AML in the post-transplant population when compared with the general population. Camos et al. (6) showed that the incidence of AML following liver transplantation is higher than expected for the general population. Similarly, Offman et al. (15) showed, in a large population study of more than 170 000 organ recipients, that organ transplantation was associated with an increased risk of AML. Specifically, the relative risk of AML in transplant recipients compared with controls matched for age, sex, and geographical origin was 5.5 for heart/lung and 2.1 for kidney recipients. 90% and 64% of heart/lung and kidney recipients, respectively, who developed PT-AML were males. The sex bias, as the authors mentioned, might have arisen from the predominance of males among transplant recipients. In the largest multicentric study to date (16), reviewing data from more than 200 000 cases of renal and 30 000 cases of heart transplantation, the standardized incidence ratios for developing AML were 1.9 and 5.1, respectively (P < 0.001 for both). Offman et al. (15) noted that while there is an excess of AML (compared with the general population) in the first 3– 4 yr after transplantation, the incidence of PT-AML diverged sharply from the expected incidence thereafter. In a comparative analysis of patients with postrenal transplantation AML (n = 16) and postliver transplantation AML (n = 13), the median interval between transplantation and AML was significantly longer for the former patients (5.5 vs. 2 yr, respectively; P = 0.03) (5). Twelve (3.4%) of the 348 patients in another large study of postrenal transplantation developed AML (17), with a latency interval of at least 11 months, and 100% disease-related mortality. In a large previous study, the increased risk of AML after heart transplantation did not begin until 3–4 yr post-transplant, whereas the risk of AML after renal transplantation started to rise earlier and in a linear manner (16). The reported cases of PT-AML in our series increased in frequency from 1974 (first case) to 2000, when the incidence peaked, and then declined again until 2013 (Fig. 1). With the rarity of PT-AML and potential publication bias, it is hard to determine whether the apparent peak around year 2000 represents a true increase in incidence. Cases from
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Figure 1 Demographics of PT-AML. The reported cases of PT-AML increased in frequency from 1974 (first case) to 2000, when the incidence peaked, and then declined again to 2013. Cases from North America and Europe comprised 84% of the entire data set (n = 50).
North America (44%) and Europe (40%) comprised 84% of the entire data set (Fig. 1; n = 50). Again, publication bias may explain this difference in incidence among continents. Table 1 shows a summary of our analysis. PT-AML occurred after transplantation of kidneys, liver, heart, and lungs in 23 (45%), 20 (39%), 6 (12%), and 2 (4%) cases, respectively. The nature of the present review does not allow for comparing different organ transplantation categories in terms of PT-AML incidence. The median age at diagnosis of AML was 50 yr, 5 yr older than a previous large report (4). The median age at diagnosis of AML increased significantly from kidney to liver to heart to lung recipients (P = 0.023). The simplest explanation for this trend is the presence of a similar trend for age at transplantation (P = 0.039). Similar
to a large previous report (4), the majority (72%) of our cases were males, again probably reflecting the typical transplant population. The median transplant-to-AML interval was 3.8 yr (similar to a large previous study reporting an estimate of 4 yr (4)) and was not different among recipients of different organ transplants (P = 0.09). More than 70% of cases of PT-AML occurred within 5 yr of organ transplantation; the incidence rapidly declined following this early-post-transplant critical period (Fig. 2, inset). Limiting the analysis to the two most common categories (renal and liver transplantations) revealed a significantly longer median transplant-toAML interval with kidney compared with liver transplant recipients (P = 0.046). The majority of cases of PT-AML after renal transplantation occurred within the first 5 yr, and the incidence rapidly diminished thereafter to make a long tail extending to up to two decades after the transplant. After liver transplantation, on the other hand, no such peak-andtail pattern was observed; all cases of PT-AML occurred within the first 8 yr post-transplant (P = 0.024; Fig. 2). There was no correlation between the transplant-to-AML interval and age at diagnosis of AML (P = 0.09). Similarly, there was no association between gender and any of the following variables: age at diagnosis of AML (P = 0.75), transplant-to-AML interval (P = 0.89), and the transplanted organ (P = 1.00). Twenty-five, 21, 3, and 2 patient(s) were receiving 2, 3, 1, and 4 immunosuppressive medications after transplantation, respectively. There was no correlation between the number of immunosuppressive medications and the following variables: age at diagnosis of AML (P = 0.88), transplant-to-AML interval (P = 0.21), and gender (P = 0.09). Not surprisingly, renal and liver transplant patients were exposed to a significantly smaller number of immunosuppressive medications than heart and lung transplant patients (P = 0.005).
Table 1 Comparison between the groups according to the transplanted organ
Age (yr)1 Males (%) Interval (yr)1 No. immunosuppressive medications (1:2:3:4) GC:Tac:MMF:Csp:azathioprine:others Incidental diagnosis (%) WBC at diagnosis of AML (n = 27)1 Pancytopenia (%) M0:M1:M2:M3:M4:M5:M6:M7 Unfavorable risk (%)
All (n = 51)
Kidney (n = 23)
Liver (n = 20)
Heart (n = 6)
Lung (n = 2)
P-value
50 (38–59) 36/50 (72) 3.8 (2.2–6.0) 26:21:2:2 45:15:8:23:27:5 10/39 (26) 7.0 (2.8–49.7) 13/31 (42) 1:3:2:9:10:4:5:2 12/33 (36)
41 (37–52) 16 (70) 4.7 (2.5–7.4) 1:12:10:0 22:1:3:9:18:2 8/19 (42) 8.9 (3–46.3) 6/15 (40) 0:1:1:3:5:1:3:0 8/14 (57)
50 (37–61) 14 (70) 3.0 (1.7–4.0) 2:13:4:1 15:13:4:7:3:1 2/14 (14) 4.4 (2.1–25.0) 5/12 (42) 1:1:1:6:4:1:0:1 3/16 (19)
58 (52–61) 4/5 (80) 4.2 (3.8–6.1) 0:0:5:1 6:0:1:6:4:2 0/4 (0) 137 (n = 1) 0/1 (0) 0:1:0:0:1:1:1:1 1/3 (33)
61 (57–61) 2 (100) 2.9 (0.8–2.9) 0:0:2:0 2:1:0:1:2:0 0/2 (0) 6.3 (n = 1) 1/2 (50) 0:0:0:0:0:1:1:0 –
0.023* 1.00 0.09 0.005** – 0.20 0.51 1.0 – 0.10
GC, glucocorticoids; Tac, tacrolimus; MMF, mycophenolate mofetil; Csp, cyclosporine. Median (interquartile range). *P < 0.05. **P < 0.01. –: too few cases to analyze.
1
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Figure 2 Transplant-to-AML interval. The median transplant-to-AML interval was 3.8 yr. More than 70% of cases of PT-AML occurred within 5 yr of organ transplantation; the incidence rapidly declined following this early-post-transplant critical period. The majority of cases of PT-AML after renal transplantation occurred within the first 5 yr, and the incidence rapidly diminished thereafter to make a long tail extending to up to two decades after the transplant. After liver transplantation, on the other hand, no such peak-and-tail pattern was observed; all cases of PT-AML occurred within the first 8 yr posttransplant.
The diagnosis of PT-AML was suspected based on incidentally observed abnormalities on complete blood count in 26% of patients. Incidental diagnosis did not have an association with the transplanted organ (P = 0.20), gender (P = 0.43), age at diagnosis of AML (P = 0.92), and transplant-to-AML interval (P = 0.65). Two of 39 patients (5.1%) presented with extramedullary disease. Pathogenesis and laboratory findings
It is reasonable to assume that diminished immune surveillance, the main mechanism responsible for post-transplant malignancies in general, could also increase the risk of development of acute leukemia (18). Chronic acceptance of the allograft reflects the iatrogenic paralysis of the immune system and the potential for leukemia emergence. Other potential mechanisms include direct mutagenic effects of immunosuppressive medications, opportunistic infections with oncogenic viruses, and chronic antigenic stimulation by the transplanted organ (19). The frequency of PT-AML was significantly correlated with the dose of azathioprine at 1 yr after transplantation in a large study by Offman et al. (15). They suggested that the ability of azathioprine to promote clonal expansion of DNA mismatch repair (MMR)-deficient myeloid cells is consistent with the role of post-transplant azathioprine in PT-AML (e.g., selection for the rare MMR-deficient, azathioprineresistant myeloid cells). Clearly, azathioprine effects are not
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the sole mechanism for PT-AML because, for example, only one of the 9 patients with PT-AML in the review of liver transplant recipients by Camos et al. (6) had received azathioprine for immunosuppression. The frequency of using specific immunosuppressive medications in each group in our series is shown in Table 1. The use of azathioprine was associated with a significantly longer median transplant-toAML interval (4.8 [IQR: 3–7.4] vs. 3.1 [IQR: 2–4.2] yr; P = 0.033). No such pattern was observed with other immunosuppressive medications. However, the use of azathioprine was significantly more common among renal compared with liver transplant patients (P < 0.01). In a regression model with transplant-to-AML interval (transformed and normalized) as the dependent variable and transplanted organ (kidney vs. liver), azathioprine use (0 vs. 1), and age at diagnosis of AML as potential predictors, none were significant independent predictors (P = 0.33, 0.24, and 0.60, respectively), suggesting that there is another factor that causes the difference in transplant-to-AML interval between renal and liver transplant cases. Because the two groups were similar in all other studied variables, we are not able, based on these data, to find the root of the difference. Finally, the median number of immunosuppressive medications was not different between groups with renal vs. liver transplants (P = 0.34). The frequency of different FAB subtypes of AML in our series was as follows (n = 36): M0 (3%), M1 (8%), M2 (6%), M3 (25%), M4 (28%), M5 (11%), M6 (14%), M7 (6%). The groups with different transplanted organs were not different in FAB subtype distribution. We then grouped different subtypes as M0/M1/M2, M3, M4/M5, and M6/M7 for more specific analysis. These subgroups were not different in the following variables: gender (P = 0.34), transplantto-AML interval (P = 0.64), transplanted organ (P = 0.58), number of immunosuppressive medications (P = 0.32), incidental diagnosis (P = 0.33), azathioprine use (P = 0.16), and unfavorable risk group (P = 0.39). There was a marginally significant association between the subgroups and age (P = 0.051). The median age at the time of diagnosis of AML increased from 41 (28–54) yr in M3 and 41 (25–58) yr in M4/M5 to 53 (49–64) yr in M0/M1/M2 and 59 (42– 64) yr in M6/M7. According to current WHO 2008 guidelines, the unfavorable risk group included patients with 5/del(5q), 7/del(7q), inv(3q)/t(3;3), abnormalities of 11q, 20q, 21q, del (9q), t(6;9), t(9;22), abnormalities of 17p, or a complex karyotype (3 or more abnormalities) (20). All other patients and patients with inv(16)/t(16;16) with or without any additional abnormalities and with t(8;21) and not part of a complex karyotype were included in the intermediate/favorable risk group. The groups with different transplanted organs were not different in the frequency of unfavorable risk disease (P = 0.10; Table 1). Patients with renal transplant had a marginally significant higher frequency of unfavorable risk
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disease than those with liver transplant (57% vs. 19%, respectively; P = 0.057). There was no association between unfavorable risk disease and any of the following: age at diagnosis of AML (P = 0.34), transplant-to-AML interval (P = 0.45), gender (P = 0.43), incidental diagnosis (P = 0.23), number of immunosuppressive medications used (P = 0.70). Although unfavorable risk disease was not significantly associated with use of any specific immunosuppressive medication, it was more common among patient who used azathioprine than those who did not (57% vs. 21%, P = 0.066). The median WBC count at presentation was not different across groups with different transplanted organs (P = 0.51) and was not associated with any other variable, including age (P = 0.35), gender (P = 0.91), number of immunosuppressive medications (P = 0.27), transplant-to-AML interval (P = 0.90), azathioprine use (P = 0.21), incidental diagnosis (P = 1.0), FAB subtypes (P = 0.07), and unfavorable risk disease (P = 0.69). Not surprisingly, the median WBC count was significantly higher in the M4/M5 subgroup than other subgroups (P = 0.017); this is consistent with the observation in the non-transplant setting that myelomonocytic and monocytic leukemias tend to present with higher WBC counts. A total of 13/31 (42%) patients were pancytopenic at the time of diagnosis of AML. There was no association between pancytopenia at presentation and the following variables: age at diagnosis of AML (P = 0.14), gender (P = 0.69), transplant-to-AML interval (P = 0.27), transplanted organ (P = 0.92), number of immunosuppressive medications (P = 0.28), azathioprine use (P = 0.46), and unfavorable risk disease (P = 0.40). However, pancytopenia was significantly less common among M4/M5 cases than other subgroups (P = 0.007). Finally, leukemia was donorderived in four patients; interestingly, all of these four cases occurred postliver transplantation. Treatment and prognosis
The feasibility of intensive induction chemotherapy is a problem in PT-AML because these patients are typically struggling with their fragile transplanted organ function and an increased treatment-related mortality (21). Although in the majority of reported cases, immunosuppressive medications were decreased or held at the time of diagnosis of AML, this was rarely sufficient. The only exception was a case of postrenal transplantation AML-M4 that went into CR simply with releasing immunosuppression (22). This case clearly demonstrates the role of the immune system in PT-AML and underscores the difficulty in balancing the need for allograft survival with myeloablative leukemic induction chemotherapy. In our series, three patients received allogeneic and one received autologous hematopoietic stem cell transplantation following chemotherapy, four died before receiving treatment,
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and one was treated only by discontinuing the immunosuppressive medications. The treatment was not available in 7 cases. The prognosis was generally poor, with a median overall survival of only 3 (95% confidence interval: 0.8–5.0) months (Fig. 3A). Similar to our series, a large previous report made an estimate of 2.6 months for median overall survival (4). There was no association between overall survival and the following variables: gender (P = 0.27), age (P = 0.34), transplant-to-AML interval (P = 0.29), number of immunosuppressive medications (P = 0.81), use of azathioprine (P = 0.12), pancytopenia at presentation (P = 0.79), and unfavorable risk disease (P = 0.23; Fig. 3B). The lack of a statistically significant effect of unfavorable risk on survival may be due to the very poor prognosis of PT-AML, requiring a substantially larger sample to demonstrate any measurable effect. The FAB subgroup M3 (acute promyelocytic leukemia) had a marginally significant longer survival than non-M3 cases (P = 0.057; Fig. 3C). After excluding cases with lung or heart transplantation, the survival curves were similar between liver and renal transplant groups (P = 0.87; Fig. 3D). Conclusions
About half of our cases occurred after renal transplantation, probably reflecting the commonness of renal transplantation in general. Similarly, more than 70% of our cases were males, probably reflecting the typical transplant population. The median age at diagnosis of AML was 50 yr, with a median transplant-to-AML interval of 3.8 yr. More than 70% of cases of PT-AML occurred within 5 yr of organ transplantation, and the incidence rapidly declined afterward. More than 25% of cases were asymptomatic at the time of presentation, while about 4% presented with myeloid sarcoma. The distribution of different FAB subgroups in our series was as following: M0/M1/M2 (17%), M3 (25%), M4/ M5 (39%), and M6/M7 (19%). Pancytopenia was present in 42% of all patients at presentation. 36% of patients had unfavorable cytogenetic risk disease. The prognosis was generally poor, with an estimated median overall survival of only 3 months. Although the frequency of unfavorable risk disease in our series was similar to the non-transplant-related AML, the prognosis was much poorer (23), suggesting that in addition to cytogenetic category, there are other factors specific to transplant patients that determine their prognosis. As we describe below, the biology of PT-AML may also be different from non-transplant-related AML. Treatment of post-transplant patients is very challenging for several reasons. Pre-existing immunosuppression at the time of diagnosis of AML increases treatment-related mortality. Unfortunately, the release of immunosuppression is not only insufficient for control of AML, but it may also be associated with graft rejection. The latter risk is particularly high in the first few years after the transplant, which is the time period with maximal incidence of PT-AML.
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A
B
C
D
Figure 3 Survival analysis. PT-AML has a poor prognosis, with a median overall survival of only 3 (95% CI: 0.8–5.0) months (A). Although overall survival appeared to be shorter with unfavorable risk disease, the difference did not reach statistical significance (P = 0.23; B). The FAB subgroup M3 (acute promyelocytic leukemia) had a marginally significant longer survival than non-M3 cases (P = 0.057; C). Survival curves were similar between liver and renal transplant groups (P = 0.87; D).
Returning to our original question of whether PT-AML is a distinct entity, our analysis provides compelling evidence in support of this hypothesis. (i) The transplant-to-AML interval follows two very different patterns between renal vs. liver transplant patients. Compared with liver transplant patients, AML following renal transplantation occurs significantly later and continues to occur longer (although at low frequencies) up to two decades after the transplant. The incidence of AML following liver transplantation approaches zero after the first 7 yr post-transplantation. We showed that the more frequent use of azathioprine after renal transplantation was not the cause for this interesting difference between the two groups. (ii) The initially high and later diminishing incidence of PT-AML seems to be associated with more immunosuppression early after trans-
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plantation and tapering of the immunosuppression over time. (iii) Although we had only a few cases of donor cell AML, all four cases occurred in liver transplant patients. Our understanding of the leukemogenic mechanisms in donor cell leukemia is nascent (24), but it appears that the recipient’s bone marrow niche and extrinsic cues influencing the marrow play an important role. Interestingly, not all donors from whom donor cell leukemia develops in the recipient develop leukemia (25), further supporting the hypothesis that recipient-specific factors are at least as important as intrinsic cell processes in donor cell leukemogenesis. (iv) Unfavorable risk disease was marginally significantly more common among renal compared with liver transplant patients and was associated, although not statistically significantly, with the use of azathioprine.
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Can the higher frequency of unfavorable risk disease in renal transplant patients be linked to their longer transplantto-AML interval compared with liver transplant patients? We hypothesize that immune surveillance against AML clones is stronger after renal compared with liver transplantation. As a result, the battle between the subclinical clone(s) and the immune system lasts longer after renal transplantation. Therefore, the AML clone(s) that most effectively evades and eventually defeats the immune system is a more resistant clone(s) and is harder to eradicate and control using conventional treatment approaches, a feature associated with unfavorable risk cytogenetics. In general, one would not expect to see differences in AML features between different organ transplantations if AML following transplantation was not different from AML in the non-transplant setting. Additionally, the standardized incidence ratios for developing AML have been estimated to be significantly higher following renal and heart transplantations than in the general population (1.9 and 5.1, respectively; P < 0.001 for both) (16). Finally, the remarkably skewed time dependence of AML following transplantation (i.e., early peak followed by rapid decline) supports PTAML, a separate entity. This pattern is similar to therapyrelated AML, which is now considered a distinct category in AML classification (26). Although the above findings, as presented, are not intended to offer irrefutable proof that PTAML is a separate entity, they do provide strong evidence that solid organ transplantation is associated with specific patterns in the natural history of AML. Heavy post-transplant immunosuppression likely plays a key role in the pathogenesis of PT-AML. Unfortunately, with the rarity of PTAML, and infeasibility of prospective clinicopathologic studies, future insights into the pathogenesis and management PT-AML are likely to remain obscure. Clearly more research is needed, perhaps in the form of a large multi-institutional collaborative database, to investigate and validate our significant findings and clarify whether some statistically non-significant or marginally significant results were due to a small sample size alone. Conflict of interest and sources of funding
The authors declare that they have no conflict of interest or sources of funding. References 1. Penn I. Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 1993;12:S328–36. 2. Penn I. Cancer in the immunosuppressed organ recipient. Transplant Proc 1991;23:1771–2. 3. Thalhammer-Scherrer R, Wieselthaler G, Knoebl P, et al. Post-transplant acute myeloid leukemia (PT-AML). Leukemia 1999;13:321–6.
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4. Kourelis TV, Boruchov A, Hull D, et al. Acute myeloid leukemia following solid organ transplantation: case report and comprehensive review. Conn Med 2012;76:151–4. 5. Cho YU, Chi HS, Park CJ, et al. Two cases of post-liver transplant acute myeloid leukemia in Korean adults: review of bibliographies and comparison with post-renal transplant acute myeloid leukemia. Ann Hematol 2008;87:513–4. 6. Camos M, Esteve J, Rimola A, et al. Increased incidence of acute myeloid leukemia after liver transplantation? Description of three new cases and review of the literature. Transplantation 2004;77:311–3. 7. Jiang N, Li H, Wang GS, et al. Acute leukemia, a rare but fatal complication after liver transplantation. Leuk Res 2009;33:1349–51. 8. Doti CA, Gondolesi GE, Sheiner PA, et al. Leukemia after liver transplant. Transplantation 2001;72:1643–6. 9. Saigal S, Norris S, Muiesan P, et al. Evidence of differential risk for posttransplantation malignancy based on pretransplantation cause in patients undergoing liver transplantation. Liver Transpl 2002;8:482–7. 10. Barrett WL, First MR, Aron BS, Penn I. Clinical course of malignancies in renal transplant recipients. Cancer 1993;72:2186–9. 11. Krueger TC, Tallent MB Jr, Richie RE, et al. Neoplasia in immunosuppressed renal transplant patients: a 20-year experience. South Med J 1985;78:501–6. 12. Sheil AG. Cancer in renal allograft recipients in Australia and New Zealand. Transplant Proc 1977;9:1133–6. 13. Huebner G, Karthaus M, Pethig K, et al. Myelodysplastic syndrome and acute myelogenous leukemia secondary to heart transplantation. Transplantation 2000;70:688–90. 14. Krikorian JG, Anderson JL, Bieber CP, et al. Malignant neoplasms following cardiac transplantation. JAMA 1978;240:639–43. 15. Offman J, Opelz G, Doehler B, et al. Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation. Blood 2004;104:822–8. 16. Gale RP, Opelz G. Commentary: does immune suppression increase risk of developing acute myeloid leukemia? Leukemia 2012;26:422–3. 17. Ho WK, Robertson MR, Macdonald GJ, et al. Association of acute leukaemia with chlorambucil after renal transplantation. Lancet 1994;343:1298–9. 18. Fahey JL. Cancer in the immunosuppressed patient. Ann Intern Med 1971;75:310–2. 19. Penn I. Development of cancer as a complication of clinical transplantation. Transplant Proc 1977;9:1121–7. 20. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC, 2008. 21. Cuthbert RJ, Russell NH, Jones PA, Morgan AG. Treatment of acute myeloid leukaemia in a renal allograft recipient: implications of cyclosporin immunosuppressive treatment. J Clin Pathol 1991;44:693–5. 22. Dixit MP, Farias KB, McQuade M, Scott KM. Acute myelo-monocytic infiltrate of the lower esophagus in a
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Supporting Information
Additional Supporting Information may be found in the online version of this article: Table S1. Summary of the reported cases of PT-AML.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
