Volume 11, Issue 7 , Pages 551-557, July 2005
Sirolimus and Thrombotic Microangiopathy after Allogeneic Hematopoietic Stem Cell Transplantation
Article Outline
Abstract
Thrombotic microangiopathy (TMA) may occur after allogeneic hematopoietic stem cell transplantation (HSCT) and is related in part to calcineurin inhibitor toxicity. We observed a higher-than-expected rate of TMA when calcineurin inhibitors were combined with sirolimus. To determine the incidence of and risk factors for TMA after HSCT, we performed a retrospective cohort analysis of myeloablative allogeneic HSCT recipients between 1997 and 2003. TMA diagnosis required the simultaneous occurrence of (1) creatinine increase >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) increased lactate dehydrogenase, and (4) no evidence of disseminated intravascular coagulopathy. A total of 111 sirolimus-exposed subjects were compared with 216 nonexposed subjects after HSCT. TMA occurred in 10.8% of the sirolimus group and 4.2% in the nonsirolimus group (odds ratio, 2.79; P = .03). Sirolimus exposure was associated with TMA earlier than in nonsirolimus patients (25 versus 58 days; P = .04). Only the use of sirolimus (exact odds ratio, 3.49; P = .02) and grade II to IV acute graft-versus-host disease (exact odds ratio, 6.60; P = .0002) were associated with TMA in regression analyses. Treatment of TMA varied among affected individuals. Renal recovery was complete in 92% of sirolimus-treated patients. Overall survival after TMA diagnosis was better for sirolimus subjects than for nonsirolimus subjects (58.3% versus 11.1%; P = .02). Sirolimus seems to potentiate the effects of calcineurin inhibitors on TMA after HSCT. TMA associated with sirolimus seems reversible and has a favorable prognosis when compared with TMA associated with calcineurin inhibitors alone. A careful monitoring strategy for TMA should be used with a sirolimus-containing graft-versus-host disease prophylaxis regimen.
Key words: Thrombotic microangiopathy , Hematopoietic stem cell transplantation , Sirolimus , Calcineurin inhibitor
Introduction
Despite significant advances in allogeneic hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) and transplant-related toxicity remain as 2 important hurdles to improved outcomes. GVHD prophylaxis with the combination of methotrexate and a calcineurin inhibitor has remained the most commonly used regimen for almost 2 decades [1]. Methotrexate is associated with significant transplant-related toxicity, including mucositis [2], pulmonary toxicity [3], and delayed engraftment [4, 5]. The calcineurin inhibitors have been associated with neurologic toxicity, renal dysfunction, and thrombotic microangiopathy (TMA) after transplantation [6, 7, 8]. TMA is a syndrome of microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction, although the exact definition varies in different published studies of the syndrome [9, 10, 11, 12, 13]. The association of TMA with cyclosporine and tacrolimus after stem cell and solid-organ transplantation is well established [9, 10, 11, 12, 14, 15].
Numerous attempts have been made to develop an effective GVHD prophylaxis regimen associated with less transplant-related toxicity [16, 17, 18, 19]. A novel macrocyclic lactone, sirolimus, has been found to have potent immunosuppressive effects in solid-organ transplantation [20, 21, 22, 23] and has been studied in stem cell transplantation [24, 25]. The use of sirolimus and calcineurin inhibitors in solid-organ and stem cell transplantation has been associated with TMA, [26, 27, 28, 29, 30, 31] and there is 1 case report of TMA related to sirolimus monotherapy in a renal transplant patient [26].
In 2 clinical trials of sirolimus in allogeneic stem cell transplantation, GVHD control was noted to be superior to historical controls; however, TMA was noted to occur with increased frequency [24, 25]. Because of this apparent increase in TMA incidence, we performed a retrospective cohort study of patients who underwent allogeneic stem cell transplantation between 1997 and 2003 at the Dana Farber Cancer Institute to determine the incidence of and risk factors for TMA.
Materials and methods
Study Design
This was a retrospective single-center cohort analysis of patients who underwent allogeneic HSCT between 1997 and 2003. Patients were included in the study cohort if they received sirolimus as a component of their GVHD prophylaxis regimen during the first 100 days after transplantation and were included in the control cohort if sirolimus was not used. All patients received either a cyclosporine-based or a tacrolimus-based immunosuppressive regimen. Patients who had undergone prior HSCT, who had T-cell depletion as GVHD prophylaxis, whose baseline creatinine was >1.5 mg/dL, or who had a diagnosis of severe veno-occlusive disease (VOD) of the liver were excluded from this analysis. Subjects for the case and control populations were accrued concurrently, although sirolimus-exposed subjects were accrued from 2000 onward only. Case and control cohort subjects were identified by review of electronic medical records.
TMA Definition
TMA was defined as the simultaneous occurrence of (1) creatinine increase >2.0 mg/dL or >50% above baseline, (2) schistocytosis (≥2 schistocytes per high-power field), (3) increased lactate dehydrogenase, and (4) no clinical evidence of disseminated intravascular coagulopathy.
Statistical Analysis
A 2-sided Fisher exact test was used to compare the baseline characteristics, acute GVHD, and the incidence of TMA between the 2 treatment cohorts. A logistic regression model was used to estimate the association of treatment groups and TMA incidence, adjusting for other factors. Overall survival was calculated by using the Kaplan-Meier method, and a 2-sided log-rank test was used to test the difference between survival curves.
Demographic (age and sex) and hematologic (underlying disease and remission status at time of transplantation) disease variables were recorded for each patient. Transplantation characteristics recorded included the conditioning regimen, donor characteristics (age, sex, HLA matched versus mismatched, and related versus unrelated), graft type (bone marrow versus peripheral blood stem cells), and GVHD prophylaxis regimen used. Multiple laboratory values were also recorded for all patients, including creatinine, unfractionated lactate dehydrogenase, coagulation parameters, and the presence of schistocytes on peripheral blood smear. Outcome parameters recorded included the occurrence of GVHD, VOD, and diffuse alveolar hemorrhage. Information gathered for all patients with TMA included the time from transplantation to the onset of TMA; peak creatinine; levels of tacrolimus, cyclosporine, and sirolimus at the onset of TMA; neurologic and cardiac signs at the time of diagnosis; treatment administered for TMA; development of chronic renal insufficiency; and the need for chronic hemodialysis. Finally, overall survival was recorded for all patients in this analysis.
Results
A total of 111 and 216 subjects were included in the sirolimus and nonsirolimus groups, respectively. The baseline characteristics of the subjects are summarized in Table 1. The 2 groups of subjects were balanced for demographic parameters; however, more subjects in the sirolimus group received peripheral blood stem cells (50.5% versus 18.1%; P < .01) and had unrelated donors (58.6% versus 42.6%; P < .01).
Table 1. Demographic Characteristics of Patients
| Characteristic | Sirolimus | Non-Sirolimus | P Value |
|---|---|---|---|
| Sample size | 111 | 216 | |
| Median age, y (range) | 40 (18–62) | 41(18–66) | .46 |
| Male, n (%) | 63(56.8%) | 117(54.2%) | .72 |
| Source of stem cells, n (%) | |||
| PBSC | 56(50.5%) | 39(18.1%) | |
| Bone marrow | 55(49.5%) | 176(81.5%) | |
| Bone marrow and PBSC | 1(0.5%) | <.001 | |
| Donor type, n(%) | |||
| MRD | 40(36%) | 115(53.2%) | |
| URD | 45(40.5%) | 70(32.4%) | |
| Mismatched related | 6(5.4%) | 9(4.2%) | |
| Mismatched URD | 20(18%) | 22(10.2%) | .007 |
| GVHD prophylaxis, n (%) | |||
| Sirolimus + tacrolimus ± Mtx | 111(100%) | 0 | |
| Tacrolimus ± Mtx ± other | 92(42.6%) | ||
| Cyclosporine ± Mtx ± other | 119(55.1%) | ||
| Other/unknown | 5(2.3%) | ||
| Acute GVHD | |||
| Grade 0–I | 84(77.1%) | 142(70.6%) | |
| Grade II–IV | 25(22.9%) | 59(29.4%) | .28 |
During the 6-year period of this retrospective analysis, 21 subjects were identified as having TMA within the first 100 days after allogeneic HSCT. Twelve subjects (10.8%) in the sirolimus group developed TMA, in comparison with 9 subjects (4.2%) in the nonsirolimus group (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.14–6.84; P = .03). Not all cases of TMA were recognized clinically at the time of onset.
Onset and Symptoms of TMA
The median time to develop TMA in the sirolimus cohort was 25 days from the time of HSCT, in comparison with 58 days for the control group (P = .01; Table 2). In addition to the requisite symptoms and signs defining TMA, 6 subjects in each group developed mental status changes, 2 subjects in each group developed congestive heart failure, and 2 subjects in the study group and 3 subjects in the control group developed seizures.
Table 2. Clinical Characteristics of TMA
| Variable | Sirolimus | Non-Sirolimus |
|---|---|---|
| Incidence | 12(10.8%) | 9(4.2%)⁎ |
| Median day of onset (range) | 25(11–69) | 58(17–91)† |
| Median peak creatinine (mg/dl) (range) | 3.9(2.1–9.3) | 2.5(2.3–5.7) |
| Mental status changes | 6(50%) | 6(67%) |
| Seizures | 2(17%) | 3(33%) |
| Congestive heart failure | 2(17%) | 2(22%) |
| Median sirolimus level (ng/mL) (range) | 6.1(2.5–33.0) | — |
| Median tacrolimus level (ng/mL) (range) | 9.9(2.8–27.4) | 9.1(8.2–12.1) |
| Median cyclosporine level (μg/L) (range) | — | 418(93–469) |
⁎ Odds ratio, 2.79; P = .03. |
† P = .04. |
Levels of the calcineurin inhibitors and sirolimus were assayed routinely. The median number of assays in the 2 weeks before TMA diagnosis were 5 (sirolimus), 6 (tacrolimus measurements in the sirolimus group), (5.5 tacrolimus measurements in the nonsirolimus group), and 5 (cyclosporine measurements in the nonsirolimus group). The median trough tacrolimus levels immediately before the onset of TMA were similar in the 2 groups (sirolimus group, 9.9 ng/mL; control group, 9.1 ng/mL; P = not significant). In patients treated with cyclosporine, the median trough level was 418 μg/L (range, 93–469 μg/L). In patients treated with sirolimus, the median level was 6.1 ng/mL, which is within the target range for our institution (3–12 ng/mL). Of the 9 sirolimus users at the time of TMA diagnosis, 7 had median levels within the therapeutic range.
Therapy of TMA
Most affected individuals were treated by dose adjustments or discontinuation of the calcineurin inhibitor, sirolimus, or both (Table 3). Of the 12 subjects in the study group, calcineurin inhibitors were discontinued in 4 subjects, and the doses were decreased in 6 subjects. Two subjects were initially switched from tacrolimus to cyclosporine, although cyclosporine was discontinued in 1 patient within days. One patient discontinued sirolimus, 8 subjects continued to receive sirolimus, and 3 subjects had previously discontinued sirolimus. Of the 9 subjects in the control group, 3 subjects discontinued calcineurin inhibitors, and the other 6 subjects continued dose-adjusted calcineurin inhibitors.
Table 3. Therapy and Outcome of TMA
| Variable | Sirolimus | Non-Sirolimus |
|---|---|---|
| Stop calcineurin inhibitor | 5(42%)⁎ | 3(33%) |
| Change to different calcineurin inhibitor | 1(8%) | 0 |
| Discontinue sirolimus | 1(8%) | N/A |
| Plasma exchange | 1(8%) | 2(22%) |
| Hemodialysis or CRRT | 3(25%) | 4(44%) |
| Chronic kidney disease† | 1(8%) | 2(22%) |
| Dialysis dependent | 1(8%) | 0(0%) |
| Death within 4 wk | 3(25%) | 5(56%) |
| Survival after TMA diagnosis | 58.3% | 11.1%‡ |
⁎ Includes one patient who changed to a different calcineurin inhibitor but subsequently discontinued all calcineurin inhibitors. |
† Chronic kidney disease was defined by a persistent increase of serum creatinine 2 mg/dL. |
‡ P = .02. |
Two subjects in each group required temporary hemodialysis. One patient who received sirolimus and 2 who did not were also treated with plasma exchange. The decision to institute plasma exchange was at the discretion of the treating physician.
TMA Outcome
Of the 9 subjects treated with sirolimus who survived more than 4 weeks after the onset of TMA, all regained normal renal function after resolution of TMA, including 1 patient treated with plasma exchange. The median time to a return of a creatinine level <2.0 mg/dL was 11 days (range, 4–17 days). Three patients in the sirolimus group required renal replacement therapy for 3, 7, and 25 days. One subject developed chronic renal insufficiency approximately 1 year after transplantation and after initial near-normalization of renal function. His renal biopsy sample revealed severe arterial sclerosis consistent with chronic microangiopathy. He is currently dialysis dependent. Five of 9 patients in the control group died within 4 weeks of TMA diagnosis. The single long-term survivor in the control group has chronic renal insufficiency.
Survival after TMA diagnosis was better for patients treated with sirolimus than for those who did not receive sirolimus (3-year survival, 58.3% versus 11.1%; log-rank P = .02; Figure 1). The median survival after diagnosis of TMA in the study group has not been reached, but it was 22 days in the control group. Among sirolimus-treated individuals, the cause of death was related to GVHD in 4 patients and to multisystem organ failure in the fifth. The diagnosis of GVHD predated the diagnosis of TMA by 5 to 29 days in this group, and all patients died with concomitant infections. Among non-sirolimus-treated patients, the cause of death was GVHD in 4, sepsis in 2, and TMA alone or with GVHD in the remaining 2. The 2 deaths at least partially attributable to TMA were in individuals who were given sirolimus to control or prevent GVHD after the diagnosis of TMA.
Figure 1.
Survival analysis of patients from the time of thrombotic microangiopathy diagnosis. Survival in the sirolimus cohort was superior to that of the nonsirolimus cohort (58.3% versus 11.1%; P = .02).
Risk Factors for TMA
The unadjusted OR for the development of TMA among patients treated with sirolimus was 2.79 (95% CI, 1.14–6.84; P = .03). The only other factor that was significantly associated with the development of TMA in univariate analyses was the prior occurrence of grade II to IV acute GVHD (unadjusted OR, 4.99; 95% CI, 1.99–12.53; P = .0006). Age, malignancy, stem cell source, and donor type were unrelated to the development of TMA. In a logistic regression model, both sirolimus use (adjusted exact OR, 3.49; 95% CI, 1.23–10.42; P = .017) and grade II to IV acute GVHD (adjusted exact OR, 6.60; 95% CI, 2.32-20.33; P = .0002) remained statistically significantly associated with the development of TMA.
Discussion
This retrospective analysis has demonstrated that the incidence of TMA within 100 days of allogeneic stem cell transplantation is increased 2.8-fold in subjects who receive sirolimus as primary GVHD prophylaxis. The incidence of TMA in this population was 10.8%. Sirolimus-associated TMA occurs earlier after stem cell transplantation but seems to have a more favorable prognosis when compared with TMA unrelated to sirolimus exposure. This finding needs to be confirmed in a larger study because of the small number of cases and the large number of potential confounding risk factors for TMA that have not been incorporated into a survival analysis.
Sirolimus is a novel immunosuppressant in allogeneic stem cell transplantation. It is generally well tolerated and is not associated with the neurotoxicity and nephrotoxicity associated with the calcineurin inhibitors. The important toxicities of sirolimus include reversible myelosuppression, hyperlipidemia [31], and pulmonary toxicity [14, 32, 33]. Sirolimus has been used as therapy for established acute and chronic GVHD [31, 34, 35] and now has demonstrated efficacy as a prophylactic agent [24, 25]; it may become routinely used in this setting.
The etiology of sirolimus-induced TMA is unknown. The pathologic finding of diffuse endothelial injury is commonly seen, but the mechanisms of this injury are unclear. One postulated mechanism is enhanced platelet activation and aggregation leading to endothelial damage [36]. Sirolimus may potentiate calcineurin-inhibitor nephrotoxicity via endothelial damage [28], possibly by a sirolimus-induced increase in the intrarenal concentration of calcineurin inhibitors [37] or via molecular mimicry of tacrolimus. Finally, both sirolimus and tacrolimus may increase the intrarenal release of the vasoconstrictor endothelin and lead to direct endothelial injury [38]. The syndrome of post-HSCT TMA is distinct from other classic microangiopathic syndromes such as thrombocytopenic purpura, because normal levels of the von Willebrand factor-cleaving protease ADAMTS13 have been demonstrated in most posttransplantation microangiopathic cases evaluated for this marker [13, 39, 40, 41, 42, 43].
The clinical risk factors for TMA are variable. Variables related to subject demographics (age and sex), the stem cell graft donor, the conditioning regimen used, and the occurrence of other posttransplantation complications have been reported to influence the incidence of TMA [13]. Because cases and controls were matched for some of these variables, we are unable to comment on the potential role of these factors; however, the use of peripheral blood stem cells and unrelated donors did not seem to be related to the development of TMA. The only factor that influenced the development of TMA in our regression model was the co-occurrence of acute GVHD, which has previously been reported [9, 44, 45, 46], although the mechanism of this association is not understood. We were unable to determine whether TMA was associated with the co-occurrence of VOD of the liver. Many of the patients diagnosed with VOD were treated with the experimental agent defibrotide, which may also be effective in the prevention and treatment of TMA [47, 48], and were thus excluded from our analysis. This agent will be the focus of a TMA prophylaxis trial in the near future. Some studies have suggested that the development of TMA is associated with increased levels of immunosuppressive agents [26, 27, 28]. In our study, before the onset of TMA, immunosuppressant levels both immediately before and within 2 weeks of the diagnosis of TMA in the sirolimus-exposed and -nonexposed groups were similar and were largely within the target therapeutic range for our institution. Because no difference in the incidence of TMA after tacrolimus or cyclosporine exposure has been reported, subjects receiving either of these compounds without sirolimus were analyzed together.
There are methodologic limitations to this study, the most important of which is the arbitrary definition of TMA we chose. As outlined in a recent review [13], there is no consensus on a definition of transplant-associated TMA. Most definitions include thrombocytopenia and renal insufficiency, both of which are common in the immediate posttransplantation setting. Furthermore, small numbers of schistocytes can also be seen early after transplantation and are not necessarily associated with microangiopathy [49, 50, 51]. Finally, a clinical picture similar to TMA can occur in association with acute GVHD and systemic infections, including cytomegalovirus, human herpesvirus 6, adenovirus, and aspergillosis [13], all of which occur frequently after allogeneic HSCT.
A second limitation is the retrospective nature of this study, which looked at patients treated over a 6-year period. Although many aspects of transplantation were unchanged during this interval, bias in this setting is inevitable. New, less nephrotoxic medications, including new antifungal medications, were introduced during this time period. HLA typing techniques were also refined, which may have contributed to a reduced incidence and severity of acute GVHD. Finally, the choice of calcineurin inhibitors changed at our institution during the time of the study: tacrolimus replaced cyclosporine for most patients treated in more recent years. Because only patients in the control arm received cyclosporine, we are unable to determine whether the choice of a calcineurin inhibitor is related to the incidence of TMA, but this has not previously been reported in the literature.
Ascertainment bias could have influenced outcomes in this study. As the use of sirolimus became more common at our institution and TMA was recognized more frequently, the diagnosis was made earlier, and therapeutic interventions were initiated at an earlier point in the disease course; this may have led to improved outcomes. Notably, many patients in the nonsirolimus control population did not have TMA diagnosed until postmortem examination or until this review was performed.
This study highlights the heterogeneity in posttransplantation TMA therapy, because no uniform approach to the management of these patients was noted, even within a single transplantation center. Some subjects only had immunosuppressant medications adjusted or held, whereas others were treated with plasma exchange. Certainly, more critically ill patients were offered plasma-exchange therapy, the role of which is unclear in this population, particularly when the etiology of the disorder is likely to be unrelated to the presence of antibodies to the ADAMTS13 protease. In the review reported by George et al. [13], the use of plasma exchange was associated with an inferior outcome, which was likely related to a selection bias of patients offered this therapy rather than to an effect of the therapy itself. To date, there is no reported prospective evaluation of plasma exchange for transplant-related TMA.
In this retrospective study, we have demonstrated that sirolimus, when used as GVHD prophylaxis with a calcineurin inhibitor after allogeneic stem cell transplantation, is associated with an increased incidence of TMA. Despite this, impaired renal function was reversible in most cases, and there was no negative effect on overall survival among patients given sirolimus as primary prophylaxis for GVHD. It is interesting to note that in patients with ongoing TMA related solely to calcineurin inhibitors, the addition of sirolimus may have been implicated in worse outcomes, because 2 patients with calcineurin-related TMA who were given sirolimus subsequently died. Because sirolimus may become widely used after allogeneic stem cell transplantation, we recommend a careful monitoring strategy by using a prespecified definition of TMA to detect early cases of TMA. We recommend early withdrawal of calcineurin inhibitors when TMA is diagnosed, because this may be sufficient to reverse the course of TMA. Re-exposure to sirolimus alone after the resolution of TMA does seem to be associated with a relapsing course of TMA.
Acknowledgments
Supported by National Heart, Lung and Blood Institute grant no. P01 HL070149-01A1 and an unrestricted educational grant from Fujisawa, Inc. C.C. is a recipient of a Rising Stars Award from the Dunkin Donuts Foundation and the Dana-Farber Cancer Institute.
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C.C. and N.L.H. contributed equally to this article.
PII: S1083-8791(05)00263-6
doi:10.1016/j.bbmt.2005.04.007
© 2005 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 11, Issue 7 , Pages 551-557, July 2005
