Biology of Blood and Marrow Transplantation 10:484-493 (2004) 䊚 2004 American Society for Blood and Marrow Transplantation 1083-8791/04/1007-0006$30.00/0 doi:10.1016/j.bbmt.2004.03.002
Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation in the Era of Reduced-Intensity Conditioning: The Incidence Is Not Reduced Avichai Shimoni, Moshe Yeshurun, Izhar Hardan, Abraham Avigdor, Isaac Ben-Bassat, Arnon Nagler The Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel Correspondence and reprint requests: Avichai Shimoni, MD, Department of Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel (e-mail:
[email protected]). Received December 16, 2003; accepted March 1, 2004
ABSTRACT Thrombotic microangiopathy (TMA) is one of the most severe complications of stem cell transplantation (SCT). Endothelial cell injury caused by the toxic effects of high-dose chemoradiotherapy is likely the primary event in pathogenesis. The incidence, clinical settings, and risk factors for TMA in the era of nonmyeloablative conditioning have not been well defined. The data on 147 consecutive SCTs in a single center were collected, and patients with TMA were identified. Patient characteristics, response to therapy, and outcome were recorded, and risk factors were determined. TMA occurred in 22 of 147 transplantations, with a projected incidence of 20% ⴞ 4%. TMA occurred in 3 clinical settings: classic multifactorial TMA, TMA associated with severe hepatic graft-versus-host disease (GVHD), and TMA associated with second SCT, with a projected incidence of 8% ⴞ 3%, 73% ⴞ 14%, and 70% ⴞ 16% of patients at risk, respectively. TMA occurred after 23% ⴞ 6% of nonmyeloablative and 16% ⴞ 5% of myeloablative conditioning regimens (not significant). Univariate analysis determined SCT from unrelated donors, SCT during advanced or active disease, second SCT within 6 months of a prior SCT, and acute GVHD as risk factors for TMA. The last 2 factors remained significant in a multivariate model. Thirty-two percent of patients responded to therapy. The peri-TMA mortality rate was 68% ⴞ 10%. Six patients had diffuse alveolar hemorrhage complicating TMA. SCT-associated TMA is a relatively common complication with unsatisfactory therapy and grim prognosis. Fludarabine-based nonmyeloablative conditioning does not confer a lesser risk for TMA. This observation may relate to the selective use of these regimens in elderly and heavily pretreated patients or to the lack of reduction of GVHD with these regimens, and fludarabine itself may be involved in causing endothelial damage. Further exploration of novel preventive and therapeutic measurements is required in high-risk settings. © 2004 American Society for Blood and Marrow Transplantation
KEY WORDS Thrombotic microangiopathy
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Stem cell transplantation
INTRODUCTION Thrombotic microangiopathy (TMA) is characterized by the classic clinical pentad of thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, renal abnormalities, and fever [1] resulting from the formation of widespread platelet thrombi within the microvasculature. Classic idiopathic TMA is associated with severe deficiency or inhibition of the plasma metalloprotease ADAMTS13 [2-4]. This protease specifically cleaves von Willebrand factor, thus reducing its multimeric size. 484
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Nonmyeloablative
Idiopathic TMA is characterized by inhibition of ADAMTS13 by an autoantibody, thus causing accumulation of unusually large von Willebrand factor multimers, which are implicated in the formation of platelet aggregates [4]. TMA is one of the most severe and devastating complications of stem cell transplantation (SCT) [5-17]. SCT-associated TMA is not related to ADAMTS13 deficiency [7,18-19]; rather, endothelial cell injury is likely the primary event in the pathogenesis [6,20]. Multiple factors contribute to endothelial damage after SCT. The initial endothelial injury is induced by
Posttransplantation TMA
the toxic effects of high-dose chemotherapy and total body irradiation given during pre-SCT conditioning. However, TMA is much more common after allogeneic SCT, occurring on average after 5% to 15% of SCTs, compared with less than 1% after autologous SCT [5-17]. The clinical severity is also higher after allogeneic SCT, for which TMA-associated mortality is on the average 50%, compared with 26% in the autologous setting [6]. Factors associated with allogeneic SCT—such as the use of cyclosporin A, acute graft-versus-host disease (GVHD), cytokine release syndromes, and infections such as with cytomegalovirus (CMV) or fungi [21]—may perpetuate endothelial cell injury and enhance the appearance of TMA. In particular, the use of cyclosporin A may have a central role in the pathogenesis of SCT-associated TMA. The importance of cyclosporine is documented by the observation of TMA after solid organ transplantation in association with its use, although this occurs with a lower incidence of approximately 5% [22]. Cyclosporine may cause direct endothelial injury [6,20,23] and may also have procoagulant activity because of increased platelet aggregation and vasoconstriction caused by a variety of effects on vascular endothelium and platelets [7]. Inflammatory cytokines involved in GVHD may mediate vascular endothelial cell injury or procoagulant activity, and the endothelial cell itself may become a target of GVHD [7]. Reduced-intensity or nonmyeloablative conditioning regimens have been recently introduced into clinical practice. These regimens were designed to allow some tumor cytoreduction, as well as sufficient immunosuppression to promote allograft engraftment and the induction of a graft-versus-malignancy effect as the primary curative therapeutic goal [24,25]. Nonmyeloablative SCT (NST) is less toxic, thus allowing the treatment of older patients and patients with comorbidities not eligible for standard ablative conditioning. The relative toxicities, GVHD rates, and overall outcome with these regimens still need to be defined. Because toxic effects of the conditioning regimen have a central role in the pathogenesis of SCTassociated TMA, it is conceivable that TMA risk after NST will markedly decrease. This study was designed to evaluate the risk factors and clinical settings of TMA in the era of NST, and the results showed that TMA risk did not decrease.
PATIENTS AND METHODS Patient Identification
Data on all allogeneic transplantations from July 1, 2000, in a single transplant center were prospectively recorded, and a data set for patients with SCTassociated TMA was established. A total of 147 allogeneic transplants were given to 132 patients with
BB&MT
various hematologic malignancies during this period. Fifteen patients treated for posttransplantation relapse with intensive chemotherapy (either ablative or nonmyeloablative) and mobilized donor lymphocytes with stem cells were considered as having a second SCT. Patients given nonmobilized donor lymphocyte infusions were not considered as having a second SCT. Thirty-three patients had at least 1 prior SCT (autologous or allogeneic). The diagnostic criteria for TMA included thrombocytopenia; either a decreasing platelet count or a failure to achieve platelet engraftment; and microangiopathic hemolysis, as evidenced by increased lactate dehydrogenase (LDH) and fragmented red blood cells observed in peripheral blood film. Neurologic symptoms and renal abnormalities supported the diagnosis but were not required. At the time of writing, the data set included 22 patients diagnosed with TMA after SCT. Conditioning Regimens
Sixty-three SCTs were considered to follow myeloablative conditioning: busulfan/cyclophosphamide (n ⫽ 37); cyclophosphamide/total body irradiation (n ⫽ 15); carmustine, etoposide, cytarabine, and melphalan (n ⫽ 7); or high-dose melphalan (n ⫽ 4). The conditioning regimen was selected on the basis of the underlying malignancy. Patients not eligible for standard ablative SCT because of advanced age, comorbidities, or extensive prior therapy (including prior SCT) and patients with chronic myeloid leukemia (CML) in first chronic phase were eligible for nonmyeloablative conditioning. Eighty-four SCTs followed a reduced-intensity regimen that consisted of a combination of fludarabine and intravenous busulfan (n ⫽ 29) or melphalan (n ⫽ 41) or other combinations (n ⫽ 14) based on the underlying malignancy. The allograft source was peripheral blood stem cells in most SCTs (n ⫽ 144) and bone marrow in a minority of SCTs (n ⫽ 3). GVHD prophylaxis consisted uniformly of cyclosporine and a short course of methotrexate. Patients with a matched unrelated or mismatched related donor SCT were given antithymocyte globulin during conditioning. Ex vivo T-cell depletion was not used. Standard institutional supportive care guidelines were followed. Acute and chronic GVHD was diagnosed, staged, and graded on the basis of standard criteria. Chimerism was assessed approximately 1 month after SCT by fluorescent in situ hybridization analysis for X and Y markers in sex-mismatched SCT and by microsatellite analysis in sex-matched SCT [26]. Definitions
Disease status was determined before SCT according to standard criteria. Early disease status included acute leukemia in first complete remission, 485
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CML in first chronic phase, multiple myeloma, and lymphoma in first remission. All other disease phases were considered advanced disease. Patients were determined as having disease in remission if they had no evidence of disease by standard criteria. In patients with acute leukemia, this required less than 5% blasts in marrow aspirate and normal blood counts. For the purpose of this analysis, patients with CML in chronic phase were included with those in remission. Complete response to therapy of TMA required resolution of symptoms attributed to TMA, increase of platelet count to ⬎50 ⫻ 109/L, and normalization of LDH. Partial response required improvement in these parameters that was not sufficient to determine complete response. Statistical Analysis
The incidence of TMA was calculated and plotted by using Kaplan-Meier analysis [27]. Patients were censored at the time of last follow-up or death or at the start of conditioning for a second SCT. Categorical risk factors for TMA incidence were compared by using the log-rank test. Variables found significant in the univariate analysis were included in a Cox proportional hazard model. Overall survival was calculated from the day of diagnosis of TMA and was plotted with Kaplan-Meier analysis.
RESULTS Patient Characteristics at Diagnosis
TMA was diagnosed in 22 patients after allogeneic SCT. The disease and patient characteristics at the time of diagnosis of TMA are outlined in Table 1. The median age at diagnosis was 43 years (range, 21-57 years). There were 17 men and 5 women with a diagnosis of acute myeloid (n ⫽ 10) or lymphoid (n ⫽ 5) leukemia, non-Hodgkin lymphoma (n ⫽ 3), multiple myeloma (n ⫽ 3), or CML (n ⫽ 1). The donors were HLA-matched siblings (n ⫽ 12) or matched unrelated donors (n ⫽ 10). Fourteen patients had TMA after NST, and 8 had TMA after ablative SCT. TMA was diagnosed a median of 30 days after SCT (range, 12-390 days). All patients were thrombocytopenic at the time of diagnosis, with a median platelet count of 14 ⫻ 109/L (range, 3-39 ⫻ 109/L). Ten patients had rapidly decreasing platelet counts, and in 12 patients, TMA was diagnosed before platelet engraftment. All patients had evidence of microangiopathic hemolysis, as evidenced by fragmented red blood cells in peripheral blood film. All patients had increased LDH (median, 716 IU/L [range, 390-1205 IU/L] and 967 IU/L [range, 481-7276 IU/L] at diagnosis and maximally during the course, respectively [normal institutional level, 100-260 IU/L]). The median bilirubin level was 3.3 mg/dL (range, 1.5-64.5 486
mg/dL) and 16.1 mg/dL (range, 2.8-64.9 mg/dL) at diagnosis and maximally during the course, respectively. The median creatinine level was 1.3 mg/dL (range, 0.7-4.9 mg/dL), and only 3 patients had a creatinine level ⬎2 mg/dL. Six patients had excessive cyclosporine levels within 1 week before diagnosis, and 4 patients were off cyclosporine therapy at the time of diagnosis of TMA. Eleven patients had neurologic symptoms during the course, such as confusion or changes in consciousness. However, most of these patients had multiple other potentially contributing factors (in particular, liver failure), and in only 2 patients (Table 1; patients 2 and 7) was neurologic dysfunction thought to be predominantly related to TMA. Fever was not considered a diagnostic criterion. Most patients had infections at or before diagnosis of TMA and were treated with antibiotics, but only 1 patient (patient 15) had a documented disseminated fungal infection. CMV reactivation was common but was not related in timing to TMA diagnosis. Clinical Settings and Predicting Factors
TMA occurred in 22 (15%) of 147 SCTs, with a projected incidence of 20% ⫾ 4% (Figure 1). TMA was diagnosed in 3 overlapping clinical settings. Nine patients had classic multifactorial TMA (Table 1; patients 1-9). The projected incidence was 8% ⫾ 3%. In 9 cases, TMA occurred in patients previously diagnosed with severe (stage III-IV) hepatic acute GVHD (bilirubin ⬎6 mg/dL) at the time of diagnosis of TMA (Table 1; patients 10-18). All of these patients, as well as 2 additional patients with less than stage III hepatic GVHD at diagnosis (patients 8 and 9, who belonged to the classic posttransplantation TMA group), had progressive jaundice (bilirubin ⬎15 mg/dL, believed to predominantly result from GVHD) during the course. Overall, TMA was diagnosed during the course of severe hepatic GVHD in 11 of 15 patients, or at a projected risk reaching 73% ⫾ 14%. Seven patients had TMA during the course of a second allogeneic SCT for post-SCT relapse, all from the original donor (Table 1; patients 16-22). Three of these patients also had severe hepatic GVHD that overlapped with the hepatic GVHD-associated TMA variant (patients 16-18). TMA occurred during 7 of 15 second allogeneic SCTs, with a projected risk as high as 70% ⫾ 16%. When all SCTs were considered, the univariate analysis identified SCT from an unrelated donor, SCT during advanced or active disease, a prior ablative SCT (allogeneic, autologous, or both) within 6 months before the current SCT (Figure 2), and acute GVHD as factors associated with the occurrence of SCT-associated TMA (Table 2). Male sex had borderline significance. A multivariate Cox regression model determined that acute GVHD and a second
Posttransplantation TMA
Table 1. Patient Characteristics at Diagnosis of TMA Patient No.
TMA Type*
Age (y)/ Sex
1
Classic
49/M
2
Classic
44/F
3
Classic
4
Disease Status†
Donor‡
53/M
ALL ref rel AML 1 ref MM
Classic
50/F
MDS
Sib
5
Classic
57/M
MM
Sib
6
Classic
22/M
MUD
7
Classic
56/M
AML ref rel NHL ref
8
Classic/hepatic
50/M
9
Classic/hepatic
52/M
10
Hepatic
45/M
11
Hepatic
40/M
12
Hepatic
34/M
13
Hepatic
33/M
14
Hepatic
37/M
15
Hepatic
28/M
16
Hepatic/2 allo
51/M
17
Hepatic/2 allo
45/M
18
Hepatic/2 allo
33/F
19
2 allo
21/M
20
2 allo
42/M
21
2 allo
23/F
22
2 allo
35/F
NHL ref NHL ref ALL CR3 2AML untreat CML CP MM ref AML CR2 AML CR2 AML pt-relapse AML pt-relapse AML pt-relapse ALL pt-relapse AML pt-relapse ALL pt-relapse ALL pt-relapse
Prior SCT§
Sib
No
MUD
No
Sib
Auto >6 mo No
MUD Sib
Auto >6 mo Auto
