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Association of recipient and donor hypercholesterolemia prior allogeneic stem cell transplantation and graft-versus-host disease
Leukemia Research 72 (2018) 74–78
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Research paper
Association of recipient and donor hypercholesterolemia prior allogeneic stem cell transplantation and graft-versus-host disease
T
⁎
Monica M. Rivera-Franco, Eucario León-Rodríguez , Isabel K. Lastra-German, Andrea A. Mendoza-Farias Stem Cell Transplantation Program, Hematology and Oncology Department, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico
A R T I C LE I N FO
A B S T R A C T
Keywords: Acute graft-versus-host disease Hypercholesterolemia Allogeneic hematopoietic stem cell transplantation
Few authors have reported a decreased frequency of acute graft-versus-host disease (aGVHD) using statins, as these medications have anti-inflammatory effects, however, to date, the direct association between high cholesterol and GVHD has not been reported. The aim of his study was to investigate the association of recipient and donor hypercholesterolemia with the incidence of aGVHD. A retrospective analysis was performed identifying allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients and donors at the National Institute of Medical Sciences and Nutrition in Mexico City between May 1999 and August 2017. The final cohort included 113 consecutive patients undergoing allo-HSCT and 110 donors with complete data. Acute GVHD was present in 24% patients. A statistically significant increase in the frequency of aGVHD associated with hypercholesterolemia in the recipients or donors (p = 0.03 and p = 0.008, respectively). Hypercholesterolemia in both, donor and recipient, was also associated with increased aGVHD compared to either patient or donor having hypercholesterolemia or neither (p = 0.002). No statistical significance was observed for other variables. To date, this is the first study associating hypercholesterolemia with aGVHD. According to our results we conclude that hypercholesterolemia in the donor, or in both, the patient and donor, is an independent factor for the development of aGVHD, however, further prospective and larger studies are needed as our results are preliminary.
1. Introduction Hypercholesterolemia leads to cholesterol accumulation in macrophages and other immune cells, promoting inflammatory responses. Also, signaling from toll-like receptors (TLRs) results in further cholesterol accumulation and increased inflammatory responses as a result of diminished cholesterol efflux, exacerbating chronic metabolic inflammation [1]. Although the links between cholesterol and inflammation are best exemplified by atherosclerosis, similar mechanisms may also contribute to other metabolic disorders such as obesity [2] or to autoimmune diseases. In this context, acute graft-versus-host disease (aGVHD) is an immunological syndrome that involves tissue damage mediated by donor lymphocytes, resulting from an imbalance between the effector and regulatory arms of the immune system that can affect the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) [3–5]. Moreover, prior T cell activation, the innate immune system is an important component of the induction of aGVHD. Also, pre HSCT conditioning regimens damage the intestinal epithelium leading to enhanced stimulation of TLRs which results in an increased cytokine
production and T-cell activation [6]. It is known that among patients undergoing allo-HSCT, some factors might determine the occurrence of aGVHD and its severity [7,8]. For instance, the presence of certain HLA alleles [9], types and properties of the transplanted T cells [10,11], immune cells signaling, induction of proinflammatory cytokines [12], among others, have been described. On the other hand, the role of the statins, which are inhibitors of HMG-CoA reductase and are widely used for the treatment of dyslipidemia, includes inhibition of this enzyme leading to decreased rates of DNA synthesis in lymphocytes [13,14] and more importantly, anti-inflammatory activity [15]. Therefore, some authors have reported a decreased frequency of aGVHD with the usage of these medications [16–20]. Nonetheless, as hypercholesterolemia is coupled with inflammation and represents an unspecific marker of low grade chronic diseases, it might trigger immunological responses such as aGVHD, however, to date, the direct association between high cholesterol and the latter has not been reported. The aim of this study was to investigate the association of hypercholesterolemia in both, alloHSCT recipients and donors and the incidence of aGVHD in a referral center in Mexico City.
⁎ Corresponding author at: Stem Cell Transplantation Program, Hematology and Oncology Department, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Vasco de Quiroga 15, Belisario Dominguez Seccion XVI, Tlalpan, 14080, Mexico City, Mexico. E-mail address: [email protected] (E. León-Rodríguez).
https://doi.org/10.1016/j.leukres.2018.07.023 Received 15 May 2018; Received in revised form 23 July 2018; Accepted 28 July 2018 Available online 30 July 2018 0145-2126/ © 2018 Elsevier Ltd. All rights reserved.
Leukemia Research 72 (2018) 74–78
M.M. Rivera-Franco et al.
2. Patients and methods
Table 1 Patient, Donor, and HSCT Demographics.
2.1. Data A retrospective analysis was performed identifying 121 patients receiving allo-HSCT at the National Institute of Medical Sciences and Nutrition in Mexico City between May 1999 and August 2017. Exclusion criteria included incomplete laboratory information of the recipient, cord blood transplants, engraftment failure or 30-day mortality. The final cohort included 113 consecutive patients undergoing allo-HSCT and 110 donors with complete data. Data such as demographic and clinical characteristics were obtained from a prospectively created institutional HSCT database or retrospectively from the Institutional medical records. 2.2. HSCT procedure For steady-state (SS-BM) and G-CSF-primed bone marrow (G-BM), HSCs were collected from donors by multiple aspirations of the iliac crests, in an operating room, under spinal anesthesia, G-CSF (10 μg/kg/ day) was administered 3 days (every 8 h) prior the procedure for the latter. For PBSC, HSCs were collected by apheresis with prior administration of G-CSF for 3 days. Most patients with hematological malignancies received reduced BUCY2 (busulfan 12 mg/kg, ORAL and cyclophosphamide 80 mg/kg, IV) [16] which is a reduced intensity conditioning regimen (RIC), the rest received other myeloablative regimens (MAC). Patients with aplastic anemia received antithymocyte globulin (ATG) and/or cyclophosphamide based conditioning regimens. Methotrexate (MTX) and cyclosporine A (CSA) were given for GVHD prophylaxis. MTX was administered IV, 15 mg/m2 day +3, and 10 mg/ m2 during days +6 and +11. None of the patients received MTX on day +1 [17]. CSA was administered IV, 1.5 mg/kg/12 h, during day -1 and adjusting according to serum levels (200–300 ng/μl) until 2005; afterwards CSA was administered orally (IV presentation was withdrawn from the market), 10 mg/kg during day -1, and 5 mg/kg starting day 0, adjusting according to therapeutic monitoring. CsA was maintained for 4 months post-transplant (8 months in aplastic anemia), and was subsequently reduced weekly (10%), until suspended, unless development of GVHD. Antimicrobial prophylaxis and supportive therapy were given according to Institutional guidelines. Patients were discharged when engraftment occurred and in the absence of infections or complications and follow-up was performed in the out-patient clinic. 2.3. Definition of endpoints NIH criteria was used to diagnose and evaluate severity of acute GVHD [21]. Total cholesterol in the recipient and the donor was documented approximately 1 month prior performing HSCT as part of the pre-transplant workup. High cholesterol was considered as total cholesterol ≥ 200 mg/dL, according to international guidelines [22].
Characteristic
n (%)
Patient gender Male Female Median age (range) Underlying disease AA ALL AML CML HL NHL MDS Others ADLD PNH EPP MPN MF FA Disease Risk Index Low Intermediate High Very high Not applicable (benign) Median infused CD34+ cell x 106/kg (range) HLA matched donor Related Unrelated (8/8 matched) Gender disparity Yes No Unknown Conditioning regimen MAC/RIC NMA Stem cell source G-BM SS-BM PBSC Cholesterol (mg/dL) prior HSCT Patient < 200 ≥200 Donor < 200 ≥200 Both < 200 ≥200 Other
63 (56) 50 (44) 31 (16-62) 24 (21) 27 (24) 14 (12) 13 (12) 3 (2.5) 3 (2.5) 18 (16) 11 (10) 1 4 1 1 2 2 14 (12) 47 (42) 18 (16) 2 (2) 32 (28) 2.00 (0.65-8.26) 108 (96) 5 (4) 58 (51) 49 (44) 6 (5) 86 (76) 27 (24) 62 (55) 29 (26) 22 (19) 88 (78) 25 (22) 83 (76) 27 (24) 65 (58) 8 (7) 40 (35)
Abbreviations: AA: Aplastic anemia; ADLD: Adrenoleukodystrophy; ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; CML: Chronic myeloid leukemia; EPP: Erythropoietic Protoporphyria; FA: Fanconi anemia; GBM: G-CSF-primed bone marrow; HL: Hodgkin lymphoma; MAC: Myeloablative conditioning regimen; MDS: Myelodysplastic syndrome; MF: Myelofibrosis; MPN: Myeloproliferative Neoplasm; NMA: Non-myeloablative conditioning regimen; PBSC: Peripheral blood stem cells; PNH: Paroxysmal nocturnal hemoglobinuria; RIC: Reduced intensity conditioning regimen; SS-BM: Steadystate bone marrow.
2.4. Statistical analysis Patient and HSCT characteristics and demographics were reported using descriptive statistics. Variables with normal distribution were compared with independent t-test or one-way ANOVA. Categorical variables were compared with the chi-square or Fisher’s exact test. For aGVHD, death and relapse without aGVHD were considered competing risks. Patients at risk to develop aGVHD excluded those with a 30-day mortality. For multivariate analysis, Cox regression was used. A p-value of < 0.05 was considered significant. SPSS v.21 (IBM, Chicago, IL) was used.
were males (n = 63, 56%). The median age was 31 years (range, 16–62). The underlying diseases were the following: acute lymphoblastic leukemia (n = 27, 24%), aplastic anemia (n = 24, 21%), myelodysplastic syndrome (n = 18, 16%), acute myeloblastic leukemia (n = 14, 12%), lymphomas (n = 6, 5%), chronic lymphocytic leukemia (n = 13, 12%), and others (n = 11, 10%). Most patients had a matched related donor (n = 108, 96%) and gender disparity was observed in 51%. Most patients received RIC or MAC (n = 86, 76%). The most frequent used stem cell source was G-BM (n = 62, 55%), followed by SS-BM (n = 29, 26%). Twenty five patients (22%) had total cholesterol
3. Results One hundred and thirteen patients were included. Most patients 75
Leukemia Research 72 (2018) 74–78
M.M. Rivera-Franco et al.
Fig. 1. (A) Increased incidence of aGVHD according to recipient hypercholesterolemia (40% vs 20%, p = 0.039); B) Hypercholesterolemia in the donor is associated with increased aGVHD (41% vs 17%, p = 0.008).
levels ≥ 200 mg/dL. From the 110 donors included in the analysis, 27 (25%) had total cholesterol levels ≥ 200 mg/dL prior the HSCT. Only in 7% cases, both patient and donor had high cholesterol levels (≥ 200 mg/dL). Table 1 shows overall patient, donor, and HSCT characteristics. Acute graft-versus-host disease was present in 27 patients (24%), grade I-II in 59%. Fig. 1A shows a statistically significant increase of aGVHD associated to hypercholesterolemia in the recipients (40% vs 20%, p = 0.039); also, as shown in Fig. 1B, hypercholesterolemia in the donors was associated with increased aGVHD (41% vs 17%, p = 0.008). Hypercholesterolemia in both, recipient and donor, was also associated with increased aGVHD compared to either patient or donor having hypercholesterolemia or neither (p = 0.002) as shown in Fig. 2. Further, a higher frequency of grade III-IV aGVHD was associated with high cholesterol in recipient and both, recipient and donor (60% and 80%, vs 28% and 33%, respectively, p = 0.09). Other variables (Table 2) such as gender, age, type of donor, gender
disparity, conditioning regimen, and HSC source were tested in a uni and multivariate analysis and no statistical significance was observed except for the latter in the univariate analysis, which was not confirmed in the multivariate analysis (OR: 2.1 CI 0.9–4.7; p = 0.06). Table 2 shows a statistically significant OR for developing aGVHD when patients, donors, or both had total cholesterol levels ≥ 200 mg/dL, OR: 2.6 CI 1.2–5.6; p = 0.01, OR: 2.2 CI 1.0–4.7; p = 0.04, and OR: 4.8 CI 1.6–14.2; p = 0.004, respectively. Other laboratory parameters (LDL, HDL, CBC, liver function, glucose, iron, ferritin) were tested and did not show any significant association with the incidence of aGVHD; also, increased frequency of chronic GVHD was not associated with hypercholesterolemia (results not shown). 4. Discussion The rate of allo-HSCT is increasing worldwide [23,24] and aGVHD remains the second leading cause of death following this procedure [25]. Over the last decade, there has been progress in understanding the pathophysiology of aGVHD which has helped to redefine this immune condition, opening possibilities for preventive and therapeutic approaches. However, to date, there is a paucity of standardized preventive measures for aGVHD and immunosuppression remains the primary pharmacologic strategy to prevent this condition. On the other hand, some preventive strategies are currently under investigation, but the majority of studies have focused on the relationship between levels and efficacy of immunosuppressive drugs. As some authors [16–20] have reported the potential role of statins in GVHD prophylaxis, these studies have not focused on cholesterol levels and have exclusively highlighted the immunomodulatory activity of these medications, such as the reduction of immune responses to auto and alloantigens. Further, other studies have exclusively reported hypercholesterolemia as a consequence of hepatic GVHD [26–28]. Therefore, to date, this is the first study associating hypercholesterolemia with aGVHD. Our results showed an increased frequency of aGVHD when total cholesterol levels were ≥ 200 mg/dL prior the HSCT, in the patient, donor, or both. Further, the multivariate analysis showed that total cholesterol levels ≥ 200 mg/dL in the donor or both, patient and donor, was a risk factor for the development of aGVHD. As other variables were tested and no significance was observed, we conclude that hypercholesterolemia prior HSCT, is an independent factor for the development of aGVHD. Also, although no statistically significance was observed, probably due to the small cohort, a higher frequency of grade
Fig. 2. Hypercholesterolemia in both, recipient and donor, associates with increased aGVHD, compared to hypercholesterolemia in either (other) or neither (63%, 33%, and 14%, respectively, p = 0.002). 76
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M.M. Rivera-Franco et al.
Table 2 Uni and multivariate analysis of factors associated with acute GVHD. Univariate
Multivariate (adjusted) Cox regression
Variable
OR (CI 95%)
p
Variable
OR (CI 95%)
p
Gender Female Recipient Age ≥ 40 HLA status Identical sibling Gender disparity None HSC Source Peripheral blood Conditioning regimen MAC/RIC Patient cholesterol ≥ 200 mg/dL Donor cholesterol ≥ 200 mg/dL Both P/D cholesterol ≥ 200 mg/dL
1.5 (0.6–3.7)
0.38
1.6 (0.6–3.8)
0.27
1.5 (0.5–4.3)
0.47
1.1 (0.4–3)
0.77
0.7 (0.4–4.3)
0.78
0.3 (0.6–1.4)
0.37
2.6 (0.9–7.0)
0.05*
2.15 (0.6–6.8)
0.21
2.6 (0.9–6.7)
0.04*
3.1 (1.2–8.05)
0.01*
9.1 (1.8–44.5)
0.002*
Sex Female Recipient Age ≥ 40 HLA status Identical sibling Gender disparity None HSC Source Peripheral blood Conditioning regimen MAC/RIC Patient cholesterol ≥ 200 mg/dL Donor cholesterol ≥ 200 mg/dL Both P/D cholesterol ≥ 200 mg/dL
– 0.7 (0.2–1.7)
0.48
2.1 (0.9–4.7)
0.06
1.4 (0.4–4.3)
0.5
2.6 (1.2–5.6)
0.01*
2.2 (1.0–4.7)
0.04*
4.8 (1.6–14.2)
0.004*
MAC: Myeloablative conditioning; P/D: Patient/donor; Ref (Reference); RIC: Reduced intensity conditioning; OR: Odds Ratio; - Not obtained; * Statistical significance.
and increased frequency of aGVHD in our study along with the scarcity of literature, further prospective studies are needed, particularly involving laboratory research to investigate the exact molecular and pathophysiological mechanisms by which hypercholesterolemia might increase the risk of developing aGVHD in patients undergoing HSCT.
III-IV aGVHD was observed when the recipient and both, recipient and donor, had cholesterol levels ≥ 200 mg/dL. We did not include nonrelapse mortality, relapse-free survival, and overall survival within our analysis as these results have been previously reported within the overall experience of our HSCT Program [29] and the primary outcome of this study was development of aGVHD. Regarding the potential mechanism that could lead to an increased risk of developing aGVHD as a consequence of hypercholesterolemia, it has been described that lipid rafts, enriched in cholesterol and sphingolipids, are essential components of cellular membranes and provide a platform for signal transduction to trigger immune and cellular responses (TLRs and B and T cell receptors) [30,31]. The most studied phenomenon associated with lipid rafts is atherosclerosis, where these microdomains of the membrane are involved in the regulation of several processes such as immune cell activation and inflammation. Alterations within the lipid composition of the cholesterol content, leads to changes in the signaling pathways [30,32]. Moreover, studies have shown that the accumulation of cholesterol in T cells from patients with systemic lupus erythematosus leads to an abnormal immune response [33]. Lipid rafts are also involved in antigen presentation playing an important role in APC-mediated T cell activation and proliferation [30,34] and the constant accumulation of lipid droplets may shift macrophages to a long-term pro-inflammatory phenotype [30]. Thus, these mentioned mechanisms [30,35,36], might lead to an increased pro-inflammatory response and might help to explain our recently established relationship between hypercholesterolemia and increased aGVHD. Finally, we acknowledge the limitations of this small study, and despite not including the treatment with statins among recipients and donors as this data was not available due to the retrospective nature of this study, we consider that high cholesterol is independent of the treatment. Moreover, as acute GVHD can contribute to the morbidity and mortality after allo-HSCT and pre-transplant regimen remains the best prophylactic measure in order to avoid development of this condition, more effective prevention strategies are needed, thus, our results suggest that normalizing the total cholesterol levels in both the recipient and the donor, prior performing a HSCT, might be an effective approach to diminish the risk of developing aGVHD, especially among populations, such as Mexico and the United States, where dyslipidemia is high [37,38]. We conclude that given the association between high cholesterol
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Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Research paper
Association of recipient and donor hypercholesterolemia prior allogeneic stem cell transplantation and graft-versus-host disease
T
⁎
Monica M. Rivera-Franco, Eucario León-Rodríguez , Isabel K. Lastra-German, Andrea A. Mendoza-Farias Stem Cell Transplantation Program, Hematology and Oncology Department, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico
A R T I C LE I N FO
A B S T R A C T
Keywords: Acute graft-versus-host disease Hypercholesterolemia Allogeneic hematopoietic stem cell transplantation
Few authors have reported a decreased frequency of acute graft-versus-host disease (aGVHD) using statins, as these medications have anti-inflammatory effects, however, to date, the direct association between high cholesterol and GVHD has not been reported. The aim of his study was to investigate the association of recipient and donor hypercholesterolemia with the incidence of aGVHD. A retrospective analysis was performed identifying allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients and donors at the National Institute of Medical Sciences and Nutrition in Mexico City between May 1999 and August 2017. The final cohort included 113 consecutive patients undergoing allo-HSCT and 110 donors with complete data. Acute GVHD was present in 24% patients. A statistically significant increase in the frequency of aGVHD associated with hypercholesterolemia in the recipients or donors (p = 0.03 and p = 0.008, respectively). Hypercholesterolemia in both, donor and recipient, was also associated with increased aGVHD compared to either patient or donor having hypercholesterolemia or neither (p = 0.002). No statistical significance was observed for other variables. To date, this is the first study associating hypercholesterolemia with aGVHD. According to our results we conclude that hypercholesterolemia in the donor, or in both, the patient and donor, is an independent factor for the development of aGVHD, however, further prospective and larger studies are needed as our results are preliminary.
1. Introduction Hypercholesterolemia leads to cholesterol accumulation in macrophages and other immune cells, promoting inflammatory responses. Also, signaling from toll-like receptors (TLRs) results in further cholesterol accumulation and increased inflammatory responses as a result of diminished cholesterol efflux, exacerbating chronic metabolic inflammation [1]. Although the links between cholesterol and inflammation are best exemplified by atherosclerosis, similar mechanisms may also contribute to other metabolic disorders such as obesity [2] or to autoimmune diseases. In this context, acute graft-versus-host disease (aGVHD) is an immunological syndrome that involves tissue damage mediated by donor lymphocytes, resulting from an imbalance between the effector and regulatory arms of the immune system that can affect the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) [3–5]. Moreover, prior T cell activation, the innate immune system is an important component of the induction of aGVHD. Also, pre HSCT conditioning regimens damage the intestinal epithelium leading to enhanced stimulation of TLRs which results in an increased cytokine
production and T-cell activation [6]. It is known that among patients undergoing allo-HSCT, some factors might determine the occurrence of aGVHD and its severity [7,8]. For instance, the presence of certain HLA alleles [9], types and properties of the transplanted T cells [10,11], immune cells signaling, induction of proinflammatory cytokines [12], among others, have been described. On the other hand, the role of the statins, which are inhibitors of HMG-CoA reductase and are widely used for the treatment of dyslipidemia, includes inhibition of this enzyme leading to decreased rates of DNA synthesis in lymphocytes [13,14] and more importantly, anti-inflammatory activity [15]. Therefore, some authors have reported a decreased frequency of aGVHD with the usage of these medications [16–20]. Nonetheless, as hypercholesterolemia is coupled with inflammation and represents an unspecific marker of low grade chronic diseases, it might trigger immunological responses such as aGVHD, however, to date, the direct association between high cholesterol and the latter has not been reported. The aim of this study was to investigate the association of hypercholesterolemia in both, alloHSCT recipients and donors and the incidence of aGVHD in a referral center in Mexico City.
⁎ Corresponding author at: Stem Cell Transplantation Program, Hematology and Oncology Department, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Vasco de Quiroga 15, Belisario Dominguez Seccion XVI, Tlalpan, 14080, Mexico City, Mexico. E-mail address: [email protected] (E. León-Rodríguez).
https://doi.org/10.1016/j.leukres.2018.07.023 Received 15 May 2018; Received in revised form 23 July 2018; Accepted 28 July 2018 Available online 30 July 2018 0145-2126/ © 2018 Elsevier Ltd. All rights reserved.
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2. Patients and methods
Table 1 Patient, Donor, and HSCT Demographics.
2.1. Data A retrospective analysis was performed identifying 121 patients receiving allo-HSCT at the National Institute of Medical Sciences and Nutrition in Mexico City between May 1999 and August 2017. Exclusion criteria included incomplete laboratory information of the recipient, cord blood transplants, engraftment failure or 30-day mortality. The final cohort included 113 consecutive patients undergoing allo-HSCT and 110 donors with complete data. Data such as demographic and clinical characteristics were obtained from a prospectively created institutional HSCT database or retrospectively from the Institutional medical records. 2.2. HSCT procedure For steady-state (SS-BM) and G-CSF-primed bone marrow (G-BM), HSCs were collected from donors by multiple aspirations of the iliac crests, in an operating room, under spinal anesthesia, G-CSF (10 μg/kg/ day) was administered 3 days (every 8 h) prior the procedure for the latter. For PBSC, HSCs were collected by apheresis with prior administration of G-CSF for 3 days. Most patients with hematological malignancies received reduced BUCY2 (busulfan 12 mg/kg, ORAL and cyclophosphamide 80 mg/kg, IV) [16] which is a reduced intensity conditioning regimen (RIC), the rest received other myeloablative regimens (MAC). Patients with aplastic anemia received antithymocyte globulin (ATG) and/or cyclophosphamide based conditioning regimens. Methotrexate (MTX) and cyclosporine A (CSA) were given for GVHD prophylaxis. MTX was administered IV, 15 mg/m2 day +3, and 10 mg/ m2 during days +6 and +11. None of the patients received MTX on day +1 [17]. CSA was administered IV, 1.5 mg/kg/12 h, during day -1 and adjusting according to serum levels (200–300 ng/μl) until 2005; afterwards CSA was administered orally (IV presentation was withdrawn from the market), 10 mg/kg during day -1, and 5 mg/kg starting day 0, adjusting according to therapeutic monitoring. CsA was maintained for 4 months post-transplant (8 months in aplastic anemia), and was subsequently reduced weekly (10%), until suspended, unless development of GVHD. Antimicrobial prophylaxis and supportive therapy were given according to Institutional guidelines. Patients were discharged when engraftment occurred and in the absence of infections or complications and follow-up was performed in the out-patient clinic. 2.3. Definition of endpoints NIH criteria was used to diagnose and evaluate severity of acute GVHD [21]. Total cholesterol in the recipient and the donor was documented approximately 1 month prior performing HSCT as part of the pre-transplant workup. High cholesterol was considered as total cholesterol ≥ 200 mg/dL, according to international guidelines [22].
Characteristic
n (%)
Patient gender Male Female Median age (range) Underlying disease AA ALL AML CML HL NHL MDS Others ADLD PNH EPP MPN MF FA Disease Risk Index Low Intermediate High Very high Not applicable (benign) Median infused CD34+ cell x 106/kg (range) HLA matched donor Related Unrelated (8/8 matched) Gender disparity Yes No Unknown Conditioning regimen MAC/RIC NMA Stem cell source G-BM SS-BM PBSC Cholesterol (mg/dL) prior HSCT Patient < 200 ≥200 Donor < 200 ≥200 Both < 200 ≥200 Other
63 (56) 50 (44) 31 (16-62) 24 (21) 27 (24) 14 (12) 13 (12) 3 (2.5) 3 (2.5) 18 (16) 11 (10) 1 4 1 1 2 2 14 (12) 47 (42) 18 (16) 2 (2) 32 (28) 2.00 (0.65-8.26) 108 (96) 5 (4) 58 (51) 49 (44) 6 (5) 86 (76) 27 (24) 62 (55) 29 (26) 22 (19) 88 (78) 25 (22) 83 (76) 27 (24) 65 (58) 8 (7) 40 (35)
Abbreviations: AA: Aplastic anemia; ADLD: Adrenoleukodystrophy; ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; CML: Chronic myeloid leukemia; EPP: Erythropoietic Protoporphyria; FA: Fanconi anemia; GBM: G-CSF-primed bone marrow; HL: Hodgkin lymphoma; MAC: Myeloablative conditioning regimen; MDS: Myelodysplastic syndrome; MF: Myelofibrosis; MPN: Myeloproliferative Neoplasm; NMA: Non-myeloablative conditioning regimen; PBSC: Peripheral blood stem cells; PNH: Paroxysmal nocturnal hemoglobinuria; RIC: Reduced intensity conditioning regimen; SS-BM: Steadystate bone marrow.
2.4. Statistical analysis Patient and HSCT characteristics and demographics were reported using descriptive statistics. Variables with normal distribution were compared with independent t-test or one-way ANOVA. Categorical variables were compared with the chi-square or Fisher’s exact test. For aGVHD, death and relapse without aGVHD were considered competing risks. Patients at risk to develop aGVHD excluded those with a 30-day mortality. For multivariate analysis, Cox regression was used. A p-value of < 0.05 was considered significant. SPSS v.21 (IBM, Chicago, IL) was used.
were males (n = 63, 56%). The median age was 31 years (range, 16–62). The underlying diseases were the following: acute lymphoblastic leukemia (n = 27, 24%), aplastic anemia (n = 24, 21%), myelodysplastic syndrome (n = 18, 16%), acute myeloblastic leukemia (n = 14, 12%), lymphomas (n = 6, 5%), chronic lymphocytic leukemia (n = 13, 12%), and others (n = 11, 10%). Most patients had a matched related donor (n = 108, 96%) and gender disparity was observed in 51%. Most patients received RIC or MAC (n = 86, 76%). The most frequent used stem cell source was G-BM (n = 62, 55%), followed by SS-BM (n = 29, 26%). Twenty five patients (22%) had total cholesterol
3. Results One hundred and thirteen patients were included. Most patients 75
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Fig. 1. (A) Increased incidence of aGVHD according to recipient hypercholesterolemia (40% vs 20%, p = 0.039); B) Hypercholesterolemia in the donor is associated with increased aGVHD (41% vs 17%, p = 0.008).
levels ≥ 200 mg/dL. From the 110 donors included in the analysis, 27 (25%) had total cholesterol levels ≥ 200 mg/dL prior the HSCT. Only in 7% cases, both patient and donor had high cholesterol levels (≥ 200 mg/dL). Table 1 shows overall patient, donor, and HSCT characteristics. Acute graft-versus-host disease was present in 27 patients (24%), grade I-II in 59%. Fig. 1A shows a statistically significant increase of aGVHD associated to hypercholesterolemia in the recipients (40% vs 20%, p = 0.039); also, as shown in Fig. 1B, hypercholesterolemia in the donors was associated with increased aGVHD (41% vs 17%, p = 0.008). Hypercholesterolemia in both, recipient and donor, was also associated with increased aGVHD compared to either patient or donor having hypercholesterolemia or neither (p = 0.002) as shown in Fig. 2. Further, a higher frequency of grade III-IV aGVHD was associated with high cholesterol in recipient and both, recipient and donor (60% and 80%, vs 28% and 33%, respectively, p = 0.09). Other variables (Table 2) such as gender, age, type of donor, gender
disparity, conditioning regimen, and HSC source were tested in a uni and multivariate analysis and no statistical significance was observed except for the latter in the univariate analysis, which was not confirmed in the multivariate analysis (OR: 2.1 CI 0.9–4.7; p = 0.06). Table 2 shows a statistically significant OR for developing aGVHD when patients, donors, or both had total cholesterol levels ≥ 200 mg/dL, OR: 2.6 CI 1.2–5.6; p = 0.01, OR: 2.2 CI 1.0–4.7; p = 0.04, and OR: 4.8 CI 1.6–14.2; p = 0.004, respectively. Other laboratory parameters (LDL, HDL, CBC, liver function, glucose, iron, ferritin) were tested and did not show any significant association with the incidence of aGVHD; also, increased frequency of chronic GVHD was not associated with hypercholesterolemia (results not shown). 4. Discussion The rate of allo-HSCT is increasing worldwide [23,24] and aGVHD remains the second leading cause of death following this procedure [25]. Over the last decade, there has been progress in understanding the pathophysiology of aGVHD which has helped to redefine this immune condition, opening possibilities for preventive and therapeutic approaches. However, to date, there is a paucity of standardized preventive measures for aGVHD and immunosuppression remains the primary pharmacologic strategy to prevent this condition. On the other hand, some preventive strategies are currently under investigation, but the majority of studies have focused on the relationship between levels and efficacy of immunosuppressive drugs. As some authors [16–20] have reported the potential role of statins in GVHD prophylaxis, these studies have not focused on cholesterol levels and have exclusively highlighted the immunomodulatory activity of these medications, such as the reduction of immune responses to auto and alloantigens. Further, other studies have exclusively reported hypercholesterolemia as a consequence of hepatic GVHD [26–28]. Therefore, to date, this is the first study associating hypercholesterolemia with aGVHD. Our results showed an increased frequency of aGVHD when total cholesterol levels were ≥ 200 mg/dL prior the HSCT, in the patient, donor, or both. Further, the multivariate analysis showed that total cholesterol levels ≥ 200 mg/dL in the donor or both, patient and donor, was a risk factor for the development of aGVHD. As other variables were tested and no significance was observed, we conclude that hypercholesterolemia prior HSCT, is an independent factor for the development of aGVHD. Also, although no statistically significance was observed, probably due to the small cohort, a higher frequency of grade
Fig. 2. Hypercholesterolemia in both, recipient and donor, associates with increased aGVHD, compared to hypercholesterolemia in either (other) or neither (63%, 33%, and 14%, respectively, p = 0.002). 76
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Table 2 Uni and multivariate analysis of factors associated with acute GVHD. Univariate
Multivariate (adjusted) Cox regression
Variable
OR (CI 95%)
p
Variable
OR (CI 95%)
p
Gender Female Recipient Age ≥ 40 HLA status Identical sibling Gender disparity None HSC Source Peripheral blood Conditioning regimen MAC/RIC Patient cholesterol ≥ 200 mg/dL Donor cholesterol ≥ 200 mg/dL Both P/D cholesterol ≥ 200 mg/dL
1.5 (0.6–3.7)
0.38
1.6 (0.6–3.8)
0.27
1.5 (0.5–4.3)
0.47
1.1 (0.4–3)
0.77
0.7 (0.4–4.3)
0.78
0.3 (0.6–1.4)
0.37
2.6 (0.9–7.0)
0.05*
2.15 (0.6–6.8)
0.21
2.6 (0.9–6.7)
0.04*
3.1 (1.2–8.05)
0.01*
9.1 (1.8–44.5)
0.002*
Sex Female Recipient Age ≥ 40 HLA status Identical sibling Gender disparity None HSC Source Peripheral blood Conditioning regimen MAC/RIC Patient cholesterol ≥ 200 mg/dL Donor cholesterol ≥ 200 mg/dL Both P/D cholesterol ≥ 200 mg/dL
– 0.7 (0.2–1.7)
0.48
2.1 (0.9–4.7)
0.06
1.4 (0.4–4.3)
0.5
2.6 (1.2–5.6)
0.01*
2.2 (1.0–4.7)
0.04*
4.8 (1.6–14.2)
0.004*
MAC: Myeloablative conditioning; P/D: Patient/donor; Ref (Reference); RIC: Reduced intensity conditioning; OR: Odds Ratio; - Not obtained; * Statistical significance.
and increased frequency of aGVHD in our study along with the scarcity of literature, further prospective studies are needed, particularly involving laboratory research to investigate the exact molecular and pathophysiological mechanisms by which hypercholesterolemia might increase the risk of developing aGVHD in patients undergoing HSCT.
III-IV aGVHD was observed when the recipient and both, recipient and donor, had cholesterol levels ≥ 200 mg/dL. We did not include nonrelapse mortality, relapse-free survival, and overall survival within our analysis as these results have been previously reported within the overall experience of our HSCT Program [29] and the primary outcome of this study was development of aGVHD. Regarding the potential mechanism that could lead to an increased risk of developing aGVHD as a consequence of hypercholesterolemia, it has been described that lipid rafts, enriched in cholesterol and sphingolipids, are essential components of cellular membranes and provide a platform for signal transduction to trigger immune and cellular responses (TLRs and B and T cell receptors) [30,31]. The most studied phenomenon associated with lipid rafts is atherosclerosis, where these microdomains of the membrane are involved in the regulation of several processes such as immune cell activation and inflammation. Alterations within the lipid composition of the cholesterol content, leads to changes in the signaling pathways [30,32]. Moreover, studies have shown that the accumulation of cholesterol in T cells from patients with systemic lupus erythematosus leads to an abnormal immune response [33]. Lipid rafts are also involved in antigen presentation playing an important role in APC-mediated T cell activation and proliferation [30,34] and the constant accumulation of lipid droplets may shift macrophages to a long-term pro-inflammatory phenotype [30]. Thus, these mentioned mechanisms [30,35,36], might lead to an increased pro-inflammatory response and might help to explain our recently established relationship between hypercholesterolemia and increased aGVHD. Finally, we acknowledge the limitations of this small study, and despite not including the treatment with statins among recipients and donors as this data was not available due to the retrospective nature of this study, we consider that high cholesterol is independent of the treatment. Moreover, as acute GVHD can contribute to the morbidity and mortality after allo-HSCT and pre-transplant regimen remains the best prophylactic measure in order to avoid development of this condition, more effective prevention strategies are needed, thus, our results suggest that normalizing the total cholesterol levels in both the recipient and the donor, prior performing a HSCT, might be an effective approach to diminish the risk of developing aGVHD, especially among populations, such as Mexico and the United States, where dyslipidemia is high [37,38]. We conclude that given the association between high cholesterol
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