Glutathione S-transferase A1 polymorphisms and acute graft-vs.-host disease in HLA-matched sibling allogeneic hematopoietic stem cell transplantation

Busulfan and the metabolites of cyclophosphamide are conjugated with glutathione and catabolized by enzymes of the cytosolic glutathione S-transferases family. There are clearly linked single nucleotide polymorphisms in the promoter region of the glutathione S-transferase A1 gene (i.e., GSTA1*A, -567T, -69C and -52G; GSTA1*B, -567G, -69T and -52A). We assessed whether the clinical outcomes, including acute graft-vs.-host disease, of 61 patients with hematological malignancies, following HLA-matched sibling allogeneic stem cell transplantation using busulfan/cyclophosphamide conditioning are altered by glutathione S-transferase A1 genotypes. Globally, grade II-IV acute graft-vs.-host disease developed in 13 patients (21%). Grade II-IV acute graft-vs.-host disease developed in 15.2% of 46 patients with GSTA1*A/*A diplotype and in 40.0% of 15 patients with GSTA1*A/*B or GSTA1*B/*B diplotype (p = 0.04). Moreover, this relationship between GSTA1*A/*A diplotypes and lower incidence of acute graft-vs.-host disease was independent of the age, gender, stem cell source, and disease status. The incidences of acute skin graft-vs.-host disease were 7% (3/46) in patients with GSTA1*A/*A and 27% (4/15) in patients without GSTA1*A/*A (p = 0.009, univariate; p = 0.01, multivariate). Acute hepatic graft-vs.-host disease developed in 6 (13%) of 46 patients with the GSTA1*A/*A diplotype and in 4 (27%) of 15 patients without this diplotype (p = 0.09, univariate; p = 0.12, multivariate). Ten patients (16%) developed hepatic veno-occlusive disease. No significant difference was found in the incidence of hepatic veno-occlusive disease between patients with and without the GSTA1*A/*A diplotype (19.6% vs. 6.7%; p = 0.24). We conclude that the GSTA1*A/*A diplotype is an independent protective factor against acute graft-vs.-host disease, especially for skin graft-vs.-host disease, and probably for hepatic graft-vs.-host disease, in patients using busulfan/cyclophosphamide conditioning. The identification of glutathione S-transferase A1 genotypes prior to allogeneic stem cell transplantation could allow conditioning regimens and graft-vs.-host disease prophylaxis to be modified to improve outcome.     

Dendritic Cell Therapies in Transplantation Revisited: Deletion of Recipient DCs Deters the Effect of Therapeutic DCs

A critical goal in transplantation is the achievement of donor‐specific tolerance, minimizing the use of immunosuppressants. Dendritic cells (DCs) are antigen (Ag) presenting cells (APCs) with capability to promote immunity or tolerance. The immune‐regulatory properties of DCs have been exploited for generation of tolerogenic/immunosuppressive (IS) DCs that, when transfer systemically, prolong allograft survival in murine models. Surprisingly, the in vivo mechanisms of therapies based on (donor‐ or recipient‐derived) ISDCs in transplantation remain unknown, given that previous studies investigated their effects in vitro, or ex vivo after transplantation. Since once injected, ISDCs are short‐lived and transfer Ag to recipient APCs, we assessed the role of recipient DCs by depleting them at the time of ISDC‐therapy in a mouse model of cardiac transplantation. The results indicate that, contrary to the accepted paradigm, systemically administered ISDCs reduce the alloresponse and prolong allograft survival, not by themselves, but through conventional DCs (cDCs) of the recipient. These findings raise doubts on the advantages of the currently used ISDC‐therapies, since the immune‐regulatory properties of the injected ISDC do not seem to be functionally relevant in vivo, and the quiescent/pro‐tolerogenic status of cDCs may be compromised in patients with end‐stage diseases that require transplantation.     

Surveillance of megakaryocytic function by measurement of CD61-exposing microparticles in allogeneic hematopoietic stem cell recipients

Rank A, Nieuwland R, Delker R, Pihusch V, Wilkowski R, Toth B, Kolb H‐J, Pihusch R. Surveillance of megakaryocytic function by measurement of CD61‐exposing microparticles in allogeneic hematopoietic stem cell recipients.
Clin Transplant 2011: 25: E233–E242. © 2011 John Wiley & Sons A/S. Abstract: Increasing evidence suggests that circulating microparticles (MP) exposing CD61 originate predominantly from megakaryocytes. Dramatic changes in megakaryocytic homeostasis are regularly observed following allogeneic hematopoietic stem cell transplantation (HSCT) and associated with transplantation‐associated complications. We studied MP plasma levels prospectively in healthy subjects (n = 10) and allogeneic HSCT recipients (n = 19) twice weekly from the start of conditioning therapy up to day 30. A total of 224 measurement points were evaluated. MP were isolated, double‐stained with annexin V and anti‐CD61, and analyzed by flow cytometry. In uncomplicated HSCT, we found a correlation between platelet and CD61‐exposing MP count, which resulted in a constant ratio of MP per platelet. The ratio was increased in patients with active hematological malignancies before transplantation and normalized during conditioning therapy. After take, the MP ratio increased, whereas infections and microangiopathic hemolytic anemia did not affect the ratio. In patients with GvHD, a decreased MP ratio was observed depending on the grade of GvHD, possibly indicating megakaryocytic damage. The MP ratio was able to discriminate between toxic, septic, and GvHD‐induced hyperbilirubinemia. We first describe CD61+ MP levels during allogeneic HSCT and postulate that the MP ratio might be a useful biomarker for the surveillance of megakaryocytes during HSCT.     

The lack of memory B cells including T cell independent IgM+ IgD+ memory B cells in chronic graft‐versus host disease is associated with susceptibility to infection

The chronic graft‐versus host disease (cGVHD) is associated with a perturbed B cell homeostasis and an increased infection rate. Aiming to determine the impact of lymphocyte subsets on cGVHD, blood samples from 98 patients at least 100 days following allogeneic haematopoietic stem cell transplantation (median 1066 days) were analyzed, serum levels of immunoglobulins measured and the incidence of severe infections retrospectively documented. Absolute CD19⁺ B cell counts, including counts of immature (CD10⁺ CD38⁺⁺ CD20⁺ IgM⁺⁺) and transitional (CD10^? CD38⁺⁺ CD20⁺ IgM⁺⁺) as well as class switched memory (CD19⁺ CD27⁺ IgM^? IgD^?) B cells in patients with active cGVHD (n = 52) were significantly decreased as compared to those with inactive (n = 18) or without cGVHD (n = 28). In addition, nonclass switched IgM⁺ memory B cells (CD19⁺ CD27⁺ IgM⁺ IgD⁺) were absent in patients with cGVHD, but not in patients with inactive (0.4 × 10⁶/l) or without (1.7 × 10⁶/l) cGVHD (both P < 0.001). In line with these results we found significantly decreased lgG levels in patients with cGVHD, which was associated with a significantly higher rate of severe infections in cGVHD patients. Our data underline the close association of diminished B cell counts with cGVHD and the onset of severe infections. The lack of IgM⁺ memory B cells in patients with cGVHD may indicate functional asplenia.     

High frequency of CD4+ CD25- CD69+ T cells is correlated with a low risk of acute graft-versus-host disease in allotransplants

Regulatory T cells (Tregs) maintain transplantation tolerance and suppress graft-versus-host disease (GvHD) in humans. We monitored 17 subjects with acute GvHD to determine whether Treg frequency correlates with acute GvHD. We found the percent of CD4(+) CD25(-) CD69(+) Tregs decreases when acute GvHD develops and increases after acute GvHD is controlled. We next sequentially studied 50 subjects receiving conventional allotransplants. We show a high frequency and increased numbers of CD4(+) CD25(-) CD69(+) Tregs are associated with a reduced risk of acute GvHD. We also show that CD4(+) CD25(-) CD69(+) Treg numbers increase substantially early after allografts and that a low percent of CD4(+) CD25(-) CD69(+) Tregs is associated with an increased risk of acute GvHD. Reconstitution of Tregs early post-transplant is associated with less acute GvHD. These data imply that CD4(+) CD25(-) CD69(+) Tregs are a novel subset of regulatory T cells that may protect against acute GvHD after allotransplants.     

Multidonor bone marrow transplantation improves donor engraftment and increases the graft versus tumor effect while decreasing graft‐versus‐host disease

In partially matched donor transplantation, mandatory T‐cell depletion (TCD) increases the risks of rejection/graft failure, relapse, and post‐transplant infections. A multi‐donor approach was offered to resolve some of these drawbacks. This hypothesis was previously tested in a TCD fully mismatched murine model. However, the effect of multi‐donor transplantation (MDT) on graft‐versus‐host disease (GVHD) and graft versus tumor (GVT) effect were never tested. To assess the safety and efficacy of MDT, we used it in non‐TCD transplantation and murine breast carcinoma model. We found that when transplanting non‐TCD MDT composed by C57Bl/6 and C3H cells into BALB/c, a consistent trichimerism is established, dominated by C57Bl/6 cells. Following MDT the study animals experienced reduced GVHD compare with those transplanted from C57Bl/6 alone, while the GVT effect was superior. We conclude that MDT may serve as a technique that suppresses GVHD while maintaining the GVT effect.     

Hyperbilirubinemia after hematopoietic stem cell transplantation: comparison of clinical and pathologic findings in 41 autopsied cases

Kagoya Y, Takahashi T, Nannya Y, Shinozaki A, Ota S, Fukayama M, Kurokawa M. Hyperbilirubinemia after hematopoietic stem cell transplantation: comparison of clinical and pathologic findings in 41 autopsied cases.
Clin Transplant 2011: 25: E552–E557. © 2011 John Wiley & Sons A/S. Abstract: Hyperbilirubinemia is often associated with morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Diagnosis of its etiology is usually made clinically among various possible causes, and analysis of histological findings as compared with the clinical diagnosis has not been performed sufficiently. We retrospectively analyzed clinical and pathological findings in 41 autopsied patients who died with hyperbilirubinemia (>2 mg/dL). Overall, liver graft‐versus‐host disease (GVHD) showed the most prominent discordance between clinical and pathological diagnoses. Only 11 of the 22 patients, considered to have liver GVHD clinically, had GVHD findings at autopsy. Serum gamma‐glutamyl transpeptidase (GGT), GGT/aspartate aminotransferase (AST) ratio, and alkaline phosphatase (ALP)/AST ratio in GVHD patients were significantly higher compared with those without GVHD (p = 0.02, <0.01, and 0.03, respectively), which was useful in clinical diagnosis of liver GVHD. Other major findings include liver invasion of the primary malignancies in 8 patients, post‐transplant lymphoproliferative disorder of the liver in two patients, and disseminated liver invasion by fungus or varicella‐zoster virus in one patient, respectively. Although analysis of clinical data is useful for narrowing diagnosis, histological analysis by liver biopsy is crucially important, especially in cases suspected of having GVHD.     

Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation

Graft‐versus‐host disease (GVHD) is a major adverse effect associated with allogeneic stem cell transplant. Previous studies in mice indicated that administration of the probiotic Lactobacillus rhamnosus GG can reduce the incidence of GVHD after hematopoietic stem cell transplant. Here we report results from the first randomized probiotic enteric regimen trial in which allogenic hematopoietic stem cell patients were supplemented with Lactobacillus rhamnosus GG. Gut microbiome analysis confirmed a previously reported gut microbiome association with GVHD. However, the clinical trial was terminated when interim analysis did not detect an appreciable probiotic‐related change in the gut microbiome or incidence of GVHD. Additional studies are necessary to determine whether probiotics can alter the incidence of GVHD after allogeneic stem cell transplant.     

骨髓移植小鼠急性移植物抗宿主病早期弥漫性肺损伤中TH17细胞的作用

目的 探讨骨髓移植小鼠急性移植物抗宿主病(aGVHD)早期肺损伤中TH 17细胞的作用和机理.方法 Balb/c小鼠为受鼠,经致死量全身照射(TBI)后,输注C57BL/6小鼠来源的骨髓细胞和脾细胞,建立aGVHD模型.实验分为3组:TBI组小鼠仅接受TBI,异基因骨髓移植(BMT)组小鼠TBI后输注供者骨髓细胞和脾细胞,常山酮(HF)组小鼠TBI后输注骨髓细胞和脾细胞,并注射HF.动态观察小鼠GVHD的表现,并进行肺组织病理学、T淋巴细胞亚群及相关细胞因子的检测.结果 移植后小鼠出现典型GVHD的表现.移植后6d时HF组肺组织病理学评分为(2.00±0.35)分,BMT组为(0.67±0.07)分.BMT组TH 1细胞占CD4+T淋巴细胞的比例为(5.53±0.11)％,TH 17细胞占(1.04±0.34)％;HF组TH1细胞占(8.61±0.21)％,TH 17细胞占(0.49±0.07)％;组间比较,差异有统计学意义(P＜0.05).两组均未检测到TH2细胞.移植后6d,BMT组白细胞介素(IL)-17A为(2.81±0.19)pg/ml,γ干扰素(IFN-γ)为(42.97±0.23) pg/ml; HF组IL-17A＜0.8 pg/ml,IFN-γ为(9.89±0.51)pg/ml;组间比较,差异有统计学意义(P＜0.05).两组均未检测到IL-10.结论 在异基因造血干细胞移植早期阻断TH17细胞及其细胞因子的分泌,导致炎症因子分泌失衡,加重肺损伤.     

The safety and efficacy of acute graft‐versus‐host disease prophylaxis with a higher target blood concentration of cyclosporine around 500 ng/mL

Cyclosporine (CsA) is the most widely used immunosuppressive agent for the prevention of acute graft‐versus‐host disease (GVHD). In a previous report, the incidence of acute GVHD was decreased by increasing the target blood concentration of CsA during a continuous infusion from 300 to 500 ng/mL without excessive toxicities. To confirm these results, we retrospectively analyzed 69 patients who received a continuous infusion of CsA at a higher target CsA level between 450 and 550 ng/mL (CsA500 group) and compared the clinical outcome with 29 patients who received CsA with a lower target concentration between 250 and 350 ng/mL (CsA300 group). The target concentration was determined based on the status of background diseases. Multivariate analysis revealed that the incidence of grade III‐IV acute GVHD was significantly lower in the CsA500 group, although the incidence of grade II‐IV acute GVHD was not different. Toxicities were equivalently observed between the two groups. Concomitant administration of voriconazole or itraconazole and higher hematocrit were identified as independent significant factors for higher concentration/dose ratio of CsA. The average dose of CsA to maintain CsA level around 500 ng/mL was higher compared with the previous study (3.4 mg/kg vs. 2.7 mg/kg at three wk), probably due to the difference in measuring method of CsA concentration. We conclude that continuous infusion of CsA with a target level between 450 and 550 ng/mL is a feasible and effective GVHD prophylaxis, but caution should be paid for the difference in measuring method.     

Modified donor lymphocyte infusion‐associated acute graft‐versus‐host disease after haploidentical T‐cell‐replete hematopoietic stem cell transplantation: incidence and risk factors

We performed a study to investigate the profile of donor lymphocyte infusion (DLI)‐associated acute graft‐versus‐host disease (GVHD) in haploidentical T‐cell‐replete hematopoietic stem cell transplantation (HSCT). A total of 124 patients receiving modified DLI after haploidentical T‐cell‐replete HSCT were enrolled. The cumulative incidence of DLI‐associated acute GVHD was 53.2% for grades II–IV and 28.4% for grades III–IV. The duration of GVHD prophylaxis after DLI was the only risk factor for DLI‐associated grades III–IV acute GVHD (p < 0.05). The cumulative incidence of grades III–IV acute GVHD in patients with prophylaxis more than six, four to six, two to four, and <2 wk were 9.3%, 14.4%, 31.6%, and 49.5%, respectively (p = 0.018). Furthermore, DLI‐associated grades III–IV acute GVHD was the only risk factor for overall survival (p = 0.038, OR   = 2.869) and transplant‐related mortality (p = 0.018, OR = 3.296) but not a risk factor for relapse after DLI (p = 0.840). This study confirms for the first time that the duration of GVHD prophylaxis after DLI is the only risk factor for the development of grades III–IV acute GVHD. Donor lymphocyte infusion with prophylaxis more than six wk was associated with a lower incidence of grades III–IV acute GVHD.     

Potential immunosuppressive function of plasma indoleamine 2,3-dioxygenase in patients with aGVHD after allo-HSCT

Given the function of indoleamine 2,3-dioxygenase (IDO) in the induction of immune tolerance as a T-cell inhibitor, we investigated whether plasma IDO levels correlate with the biological activity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Plasma levels of IDO were monitored by ELISA in 147 samples from 65 patients who fulfilled the diagnostic histopathological and/or clinical criteria of aGVHD and 16 episodes of infection after allo-HSCT. Elevated plasma IDO levels were associated with occurrence of infection or mild aGVHD (grade I-II). Most patients with grade III-IV aGVHD had relatively low levels of IDO compared to those with mild aGVHD or infection. Responses of aGVHD to immunosuppressive therapy were associated with a decrease in IDO levels in the majority of patients with mild aGVHD, whereas secondary infection was characterized by persistent or increased IDO levels after treatment. Although plasma IDO levels may indicate the severity and outcome of aGVHD and point to appropriate therapies through its function in immune tolerance, it is not aGVHD specific and may not be a distinguishing biomarker of aGVHD.     

The Programmed Death (PD)‐1/PD‐Ligand 1 Pathway Regulates Graft‐Versus‐Host‐Reactive CD8 T Cells After Liver Transplantation

Acute graft‐versus‐host disease (aGVHD) is a life‐threatening complication after solid‐organ transplantation, which is mediated by host‐reactive donor T cells emigrating from the allograft. We report on two liver transplant recipients who developed an almost complete donor chimerism in peripheral blood and bone marrow‐infiltrating T cells during aGVHD. By analyzing these T cells directly ex vivo, we found that they died by apoptosis over time without evidence of rejection by host T cells. The host‐versus‐donor reactivity was selectively impaired, as anti‐third‐party and antiviral T cells were still detectable in the host repertoire. These findings support the acquired donor‐specific allotolerance concept previously established in animal transplantation studies. We also observed that the resolution of aGVHD was not accompanied by an expansion of circulating immunosuppressive CD4/CD25/FoxP3‐positive T cells. In fact, graft‐versus‐host‐reactive T cells were controlled by an alternative negative regulatory pathway, executed by the programmed death (PD)‐1 receptor and its ligand PD‐L1. We found high PD‐1 expression on donor CD4 and CD8 T cells. In addition, blocking PD‐L1 on host‐derived cells significantly enhanced alloreactivity by CD8 T cells in vitro. We suggest the interference with the PD‐1/PD‐L1 pathway as a therapeutic strategy to control graft‐versus‐host‐reactive T cells in allograft recipients.     

Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on prognosis

Hyperlipidemia is one of the late complications after allogeneic stem cell transplantation (SCT). Although intrahepatic cholestasis caused by chronic graft‐versus‐host disease (GVHD) or calcineurin inhibitors has been considered as possible etiologies, its prevalence, risk factors, and impact on prognosis have not been investigated well. We performed a retrospective analysis of 194 patients who underwent allogeneic SCT between 1995 and 2008 in our institute and survived more than 100 d after SCT. Overall, 83 (42.8%) and 99 (50.8%) patients developed hypercholesterolemia (≥240 mg/dL) and hypertriglyceridemia (≥200 mg/dL), respectively. In multivariate analysis, the development of chronic GVHD (hazard ratio [HR] 2.04, p < 0.05) and steroid use (HR 2.24, p < 0.01) were independently associated with hypercholesterolemia, while administration of calcineurin inhibitors was not. As for the prognostic impact, multivariate analysis showed that the patients with hypercholesterolemia had a tendency of lower rate of relapse (HR: 0.44, p = 0.07). There was no difference in non‐relapse mortality or overall survival between the groups. In conclusion, the development of hypercholesterolemia is regarded as one of the symptoms accompanied with chronic GVHD and might indicate a better control of the primary disease.     

CT鉴别诊断造血干细胞移植后胃肠道移植物抗宿主病与机会性感染性肠炎

目的 观察CT鉴别诊断造血干细胞移植(HSCT)后胃肠道移植物抗宿主病(GI-GVHD)与机会性感染性肠炎的价值。方法 回顾性分析59例HSCT后出现胃肠道症状且经内窥镜下组织活检病理确诊GI-GVHD(GI-GVHD组,n=31)或机会性感染性肠炎(机会性感染性肠炎组,n=28)患者,观察其CT表现差异。结果 GI-GVHD组CT显示肠壁增厚、肠壁强化、肠管积气及肠外CT表现肠周淋巴结增生、胆囊炎、膀胱炎或膀胱出血率均高于机会性感染性肠炎组(P均＜0.05),而CT显示多灶性肠壁炎症及肠系膜水肿率组间差异均无统计学意义(P均＞0.05)。结论 CT有助于鉴别诊断HSCT后GI-GVHD与机会性感染性肠炎。     

Long‐term outcomes of antithymocyte globulin in patients with hematological malignancies undergoing myeloablative allogeneic hematopoietic cell transplantation: a systematic review and meta‐analysis

Antithymocyte globulin (ATG) has shown efficacy in preventing acute GVHD (aGVHD) in allogeneic hematopoietic cell transplantation (allo‐HCT), but its efficacy in chronic GVHD (cGVHD) and long‐term outcomes remains controversial. We conducted a systematic review and meta‐analysis to evaluate potential benefit and risk of prophylactic ATG use in myeloablative HCT. We searched Pubmed, EMBASE, Cochrane databases, and included 10 trials (two RCTs and eight retrospective) comparing ATG use vs. control with a total of 1859 patients. The median follow‐ups were over two yr. Outcomes assessed included overall cGVHD, extensive cGVHD, overall survival (OS), disease‐free survival, relapse, and causes of death. Our results showed ATG significantly decreased overall cGVHD (RR = 0.59; 95% CI: 0.53–0.66, p < 0.00001), extensive cGVHD (RR = 0.34; 95% CI: 0.25–0.47, p < 0.00001). Pooled results also showed ATG use was associated with a marginal increased risk of relapse (RR = 1.28; 95% CI: 1.01–1.63, p = 0.04), and a non‐inferior OS (HR = 0.86; 95% CI: 0.74–1.01, p = 0.06). We conclude prophylactic use of ATG exerts a favorable effect in reducing cGVHD without survival impairment in a long term, although a higher relapse rate is a major threat.     

No effect of HLA‐C mismatch after allogeneic hematopoietic stem cell transplantation with unrelated donors and T‐cell depletion in patients with hematological malignancies

HLA‐C mismatch in unrelated donor's hematopoietic stem cell transplantation (HSCT) has been associated with poor patient outcome. However, the impact of HLA‐C mismatch in the context of HSCT combined with in vivo T‐cell depletion remains unclear. We therefore performed a single‐center, retrospective analysis of the clinical outcome on patients with hematological malignancies treated with allo‐HSCT, who underwent T‐cell depletion. The majority of the patients (n=276) received a HLA‐A, HLA‐B, HLA‐DRB1‐matched graft that were either also HLA‐C matched (n=260), or patients with the permissive HLA‐C*03:03/03:04 mismatch (n=16), while the remaining patients (n=95) received a HLA‐C‐mismatched graft (excluding HLA‐C*03:03/03:04 mismatches). We did not observe any significant differences between the HLA‐C‐matched patients (including the permissive HLA‐C*03:03/03:04 mismatch) and the HLA‐C‐mismatched patients regarding cumulative proportion surviving, graft failure, relapse‐free survival, relapse, or acute graft‐versus‐host disease. Our data suggest that in the context of high dose T lymphocyte‐depleting agents, HLA‐C matching is not essential for patients with hematological malignancies.     

A review of late complications of allogeneic hematopoietic stem cell transplantations

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is an effective and curative treatment of different malignant and non‐malignant diseases. Early transplant‐related mortality after allo‐HSCT has decreased with reduced‐intensity conditioning regimens and effective anti‐infectious treatments, but late transplant‐related mortality is still a problem. Physicians are now paying more attention to late complications that may worsen the quality of life of many transplant recipients. Chronic graft versus host disease (cGVHD) is one of the major causes of late transplant‐related mortality after allo‐HSCT. This review discusses recent advances that have been made in clinical evaluation and treatment of late transplant‐related complications including cGVHD. The different sites of involvement are organs, especially the skin and eye, and the gastrointestinal, endocrinologic, metabolic, renal, cardiologic, pulmonary, connective tissue, and neurological systems. In addition, this review includes infections and secondary malignancies in post‐transplant settings that worsen quality of life in long‐term follow‐ups.