Liver Graft-versus-host Disease Research Articles

Gastric Antral Vascular Ectasia As a Manifestation of Liver Graft Versus Host Disease Responsive to Ruxolitinib

Gastric Antral Vascular Ectasia As a Manifestation of Liver Graft Versus Host Disease Responsive to Ruxolitinib

Post-Transplant Cyclophosphamide Combined with Brilliant Blue G Reduces Graft-versus-Host Disease without Compromising Graft-versus-Leukaemia Immunity in Humanised Mice.

Allogeneic haematopoietic stem cell transplantation (HSCT) leads to the establishment of graft-versus-leukaemia (GVL) immunity, but in many cases also results in the development of graft-versus-host disease (GVHD). This study aimed to determine if P2X7 antagonism using Brilliant Blue G (BBG) could improve the beneficial effects of post-transplant cyclophosphamide (PTCy) in a humanised mouse model of GVHD, without comprising GVL immunity. NOD.Cg-Prkdcscid Il2rgtm1Wjl (NSG) mice were injected with human peripheral blood mononuclear cells (PBMCs) (Day 0), then with cyclophosphamide (33 mg/kg) on Days 3 and 4, and with BBG (50 mg/kg) (or saline) on Days 0-10. PTCy with BBG reduced clinical GVHD development like that of PTCy alone. However, histological analysis revealed that the combined treatment reduced liver GVHD to a greater extent than PTCy alone. Flow cytometric analyses revealed that this reduction in liver GVHD by PTCy with BBG corresponded to an increase in human splenic CD39+ Tregs and a decrease in human serum interferon-γ concentrations. In additional experiments, humanised NSG mice, following combined treatment, were injected with human THP-1 acute myeloid leukaemia cells on Day 14. Flow cytometric analyses of liver CD33+ THP-1 cells showed that PTCy with BBG did not mitigate GVL immunity. In summary, PTCy combined with BBG can reduce GVHD without compromising GVL immunity. Future studies investigating P2X7 antagonism in combination with PTCy may lead to the development of novel treatments that more effectively reduce GVHD in allogeneic HSCT patients without promoting leukaemia relapse.

Dual Functions of Mitochondrial Calcium Uniporter in T Cell Alloimmunity

Despite pharmacological prophylaxis using calcineurin inhibitors, graft-versus-host disease (GVHD) still occurs in patients undergoing allogeneic hematopoietic stem cell transplantation. However, the mechanism that underlies the breakthrough of alloreactive T cell responses following calcium signaling inhibition remains poorly defined. The mitochondrial calcium uniporter (MCU), which is located in the inner mitochondrial membrane, controls Ca2+ uptake into the mitochondria matrix. Past dogma suggested that lack of mitochondria calcium uptake would compromise T cell immune response due to suboptimal NFAT activation upon TCR ligation. However, the exact role of MCU in the regulation of alloreactive T cell responses has not been previously determined. Here, we demonstrate dual functions of MCU in alloreactive T cell response and GVHD maintenance, highlighting MCU as a potential novel target to manipulate T cell alloreactivity. Using T cell-specific Mcu conditional knockout C57/BL6 (B6) mice (Mcu-cKO), we found that compared to WT T cells, B6 Mcu-cKO T cells induced less severe GVHD in Balb/c mice, with prolonged survival and significantly lower number of donor effector cells in the spleen and liver early after transplantation. Surprisingly, these Mcu-cKO T cell recipients developed severe liver GVHD by 60 days after transplantation, as evidenced by extensive lymphocytic infiltration in the liver, while to a lesser extent in the skin and intestine in these GVHD mice. Flow cytometric analysis of donor T cells, which were harvested between 5 and 8 weeks after transplantation, showed that Mcu-cKO T cells retained the IFN-g- and GM-CSF-producing capacity, but acquired stronger capacity of producing the cytotoxic molecule granzyme B. To comprehensively delineate the role of MCU in allogeneic T cell response, we used MHC-identical but minor histocompatibility antigen (miHA)-mismatched B6-to-Balb/b GVHD model, in which alloreactive CD8+ T cells can be identified with H60 peptide/MHC class-I dimer staining. Similarly, loss of Mcu in T cells caused less severe GVHD, attributed to the decreased number of H60+CD8+ effector T cells that showed impaired proliferation capacity. RNA-seq analysis of liver-infiltrating H60+CD8+ T cells revealed that Mcu ablation resulted in decreased expression of cell proliferation genes (Pclaf, Cdc45, Top2a, Cdca8, etc), increased expression of genes (Cd7, Bcl2, CD96, Eomes, Ezh1, etc) associated with memory T cells. These results demonstrated that Mcu is required for the expansion of alloreactive T cells, but restricts their memory-associated transcriptional programs during GVHD maintenance. Further characterization showed these alloreactive Mcu-cKO T cells produced higher levels of tissue migration molecules (CCR9, CCR5, etc) and lower death molecule (Lpin1) than their WT counterparts. Using gain-of-function strategy of retroviral Mcu overexpression in T cells (McuOE), we found McuOE CD8+ T cells displayed enhanced effector differentiation represented by higher expression of effector molecules (Ifng), decreased expression of stemness and memory associated molecules (Tcf7, Id3), and reduced expression of migration molecules (CCR9, CXCR3, etc). The cultured McuOE CD8+ T cells contracted earlier than WT. These results were further validated in vivo using the B6-to-Balb/c GVHD model. These data demonstrate a negative regulatory role of MCU in the tissue migration and persistence of alloreactive T cells. Notably, human T cells from patients with severe GVHD produced lower levels of MCU protein compared to that of non-GVHD patients. Our findings identified for the first time the dual functions of MCU in the regulation of T cell alloimmunity. MCU-mediated mitochondria calcium uptake promotes early expansion of alloreactive T cells but restricts the expression of memory-associated gene programs and tissue migration molecules. Strategies of enhancing MCU functionality in alloreactive T cells could potentially reduce their memory potential and tissue infiltration capacity, thereby reducing GVHD.

Iron Dys-Homeostasis Contributed to Liver Gvhd after Allogeneic Hematopoietic Stem Cell Transplantation

Graft-versus-host disease (GVHD), which results from immunological attack to recipient organs or tissues (such as the skin, liver and gut) by donor allogeneic T cells, limits the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A correlation of high serum ferritin levels with increased mortality after allo-HSCT has been suggested by several analyses. While the role of iron dys-homeostasis in the risk of GVHD remains unclear. Whether iron dys-homeostasis contributes to the development of GVHD or iron dys-homeostasis is only a result of severe GVHD remains unknown. To assess the status of iron metabolism during GVHD following allo-HSCT, we established aGVHD mouse model by transplantation of T cell-depleted bone marrow (TCD BM) with or without splenic T cells from C57BL/6 (B6) mice to BALB/c mice after being lethally irradiated. By 28 days post-transplantation, when aGVHD stable developed, the serum iron level was significantly higher in aGVHD group compared with control. Meanwhile, ferrous-ion load in aGVHD-involved liver was also increased, while the total iron load did not differ significantly in aGVHD-involved liver compared with control. The ferrous-ion load as well as the total iron load in intestine, lung and spleen were comparable between aGVHD group and control group. To further determine the dysregulation of iron metabolism during liver aGVHD, we detected the expression levels of pivotal iron regulatory genes in liver and duodenum. The expression levels of transferrin receptor 1 ( Tfr1) and divalent metal transporter 1 ( Dmt1) were significantly upregulated in aGVHD-involved liver, which contributed to ferrous-ion overload in the liver aGVHD. Besides, Ferroportin 1 was down-regulated in aGVHD-involved duodenum, which is the result of the upregulated hepcidin ( Hamp1) in liver. Our data suggested that the increased serum iron in aGVHD was not related to iron absorption by duodenum, but may be associated with ineffectively use of iron, which was caused by the impaired marrow function after myeloablative conditioning. To explore whether ferrous-ion overload in liver would lead to induction of reactive oxygen species (ROS) via the Fenton reaction, and eventually results in liver damage during aGVHD, we detected the activity of superoxide dismutase (SOD) and the load of thiol and lipid peroxidation product, malondialdehyde (MDA). The activity of SOD and thiol load both decreased significantly in aGVHD-involved liver, while the serum MDA level increased in aGVHD group, indicating that iron dys-homeostasis may aggravate liver GVHD damage by induction of lipid peroxidation injury. Finally, to explore how iron overload affect GVHD, we fed recipient mice with high-iron diet and low-iron diet since three weeks before transplantation, respectively. The survival rates and GVHD score were significantly worse in high-iron diet group compared with normal-iron diet group. Interestingly, low-iron diet didn't show survival benefit compared with the normal-iron diet. This suggests that excessive iron deficiency is not beneficial for preventing and treating GVHD. Thus, we applied apo-transferrin (apo-Tf) administration to receipt mice, which can render the poorly soluble non-transferrin bonding iron (NTBI) into a soluble transferrin-bound form, and prevent iron from being rapidly uptake by the liver. The administration of apo-Tf alleviated the organ damage during aGVHD, and reduced the infiltration of CD4 +IFN-γ +T cells, CD4 +IL17 +T cells and CD8 +IL17 +T cells in target organs such as intestine, liver and lung. These data suggested that ferrous-ion overload leads to the increase of NTBI, which aggravate GVHD tissue damage. Our findings reveal a novel mechanism of iron dys-homeostasis during the development of liver aGVHD, which may reveal promising therapeutic targeting in the prevention and treatment of liver aGVHD.

Post-Transplant Cyclophosphamide, Abatacept, and Vedolizumab to Prevent Graft-Versus-Host Disease after Hematopoietic Stem Cells Transplantation from Haploidentical Donors in Children with Acute Leukemia: Results of a Prospective Trial

Introduction Graft-versus-host disease (GvHD) remains a crucial complication associated with significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). High-dose post-transplantation cyclophosphamide (PTCy) targets alloreactive donor T cells proliferating early after HSCT, promotes regulatory T cells, and prevents severe GVHD. The effectiveness of PTCy-based regimens varies depending on the graft source and intensity of the preparative regimen. Improvement of GVHD control with novel targeted agents, added to the backbone of PTCy, could further increase the safety of HSCT and reduce the morbidity and complications of standard regimens of pharmacological immune suppression. In this pilot trial, we evaluated the safety and efficacy of abatacept and vedolizumab in unmanipulated haploidentical transplantation among children with leukemia. Materials and methods A total of 54 pts with acute leukemia (AML- 18, ALL-36, 26 female, 28 male, the median age at HSCT - 7,4 years (0,4-16,8), underwent unmanipulated allogeneic bone marrow (BM) (n=53) or peripheral blood stem cell (PBSC)(n=1) transplantation between March 2022 and May 2023. All donors were haploidentical relatives, represented Disease status at transplant was CR1 in 25 pts, CR³2 in 29 pts. For all patients, it was the 1-st transplantation. All patients received myeloablative conditioning, either TBI-based (n=30) or 24 treosulfan-based (n=24), with either cyclophosphamide (n=47) or etoposide (n=7) as a second agent. Prophylaxis of graft-versus-host-disease (GVHD) consisted of CsA from day-1 to day 180, 50 mg/kg of Cph on days +3 and +4, abatacept at 10 mg/kg on days +5, +14, +28, +45, +60 and vedolizumab at 10 mg/kg (capped at 300 mg) on days -1, +14, +28. The median dose of CD34+ cells was 4,7 x10 6/kg (range 1,2-17), and the CD3 dose was 42 x10 6/kg. Results Primary engraftment was achieved in 53 (98%) pts; the median time to neutrophil and platelet recovery was 20 and 23 days, respectively. All engrafted pts had verified morphologic remission and achieved complete donor chimerism by day +30. One patient failed to engraft, relapsed, and required rescue with a second HSCT from an alternative donor. The regimen was generally well tolerated. Acute toxicity consisted of grade III-IV mucositis (n=5); grade II-III hemorrhagic cystitis (n=4); grade III-V veno-occlusive disease (n=2) (all cases of VOD developed after pre-HSCT use of inotozumab); bloodstream infections (n=8). Four patients were admitted to the intensive care unit due to septic events or VOD. The median follow-up time for survivors was seven months (range: 1 -15). Transplant-related mortality was 2% (95% CI:0,3-14): one patient with ALL previously treated with inotozumab died in CR due to consequences of severe VOD on day + 60. The cumulative incidence of aGVHD grade II-IV was 36% (95% CI, 25 - 52), and grade 3-4 was 9% (95% CI, 4 - 22). In 13 cases, aGVHD was limited to skin: grade 2 (n=12), grade 4 (n=1), in two cases to the gut: grade 3(n=1), grade 4(n=1), three patients had skin and gut GVHD: grade 2 (n=2), grade 3(n=1) and one had skin and liver GVHD grade 3. The cumulative incidence of gut aGVHD grade II-IV was 9% (95% CI, 4 - 22). Eleven patients with GVHD responded to first-line immunosuppressive treatment, while 8 received additional therapy. The cumulative incidence of relapse was 11% (95%CI:5-26) in the entire cohort. EFS and OS were 89% (95%CI: 79-97) and 98% (95%CI: 94-100). The GVHD- and relapse-free survival was 78% (95%CI:67-88). Conclusion Our data suggest that adding vedolizumab and abatacept to the PTCy-based GVHD prophylaxis backbone is well tolerated and may reduce the incidence of gut GVHD among children with acute leukemia grafted from haploidentical donors. This approach can be further developed to reduce exposure to calcineurin inhibitors and deploy additional anti-leukemia effectors after HSCT.

Low Dose Ruxolitinib in Indian Haplo-Identical Transplant Patients with Steroid Refractory Acute Graft Versus Host Disease

Background: The number of allogeneic bone marrow transplants done in India is increasing by year. Unlike west, this region had got its own unique complications in the post-transplant period especially multi drug resistant gram negative bacterial sepsis reflecting in a higher transplant related mortality. With increasing number of Haplo-identical transplants, the problem of steroid refractory Graft versus host disease (GVHD) is a major reason for post-transplant morbidity and mortality. As most available immunosuppressive agents worsen cytopenia and in turn sepsis, we need a relatively safer method of managing steroid refractory GVHD in our setting. In this observational study, we used a lower dose of 5mg per day Ruxolitinib for a period of minimum 60 days post-transplant to look into clinical benefit. This dose was chosen considering the recovering platelet count and financial considerations in our resource limited setting. Method: This observational study was conducted from July 2019 to January 2022. A total of 11 steroid refractory GVHD Haploidentical transplant patients were chosen for data analysis that completed the scheduled dosage regimen of Ruxolitinib. Nine out of 11 patients were Acute Myeloid leukemia and two were Acute Lymphoblastic leukemia. The standard conditioning regimen in all was Fludarabine / Busulfan & Cyclophosphamide based conditioning. Additional GVHD medications used were PTCy, Tacrolimus, MMF and steroids with oral budesonide. Tab Ruxolitinib was started around Day +5 post steroids in people who were fitting into steroid refractory acyte GVHD at a fixed dose of 5mg OD for a minimum period of ten weeks. Two cases had one week dose interruption due to cytopenia. Results : At start of Ruxolitinib seven patients had Grade III gut and liver GVHD and rest four had grade II GVHD. Skin was grade II in all patients. When evaluated at Day +58 of Ruxolitinib, all patients were alive and nine of them were on tapering doses of steroids. All continued Tacrolimus at therapeutic doses. No excess bleeding or cytopenia requiring transfusion support happened during this period. As mentioned earlier two cases Ruxolitinib was stopped in view of platelet counts going below 20,000. On evaluation at day +100 post transplant, two patients continued to have grade II Liver, gut and skin GVH and one patient expired on day +48 to sepsis. Rest of eight patients had a Grade I skin, liver and gut GVHD and were able to continue Ruxolitinib further. We started Ruxolitinib taper in cases where steroids were stopped. As case numbers were very low and it's a pilot observation study, we didn't do detailed statistical analysis which may be misleading and give false promises. Conclusion: In our setup, we were finding it a difficulty to use the prescribed 10mg BD Ruxolitinib dose in adults due to fear of worsening cytopenia /sepsis and financial toxicity. We tried to observe the benefit of a lower dose in steroid refractory GVHD post Haplo-identical bone marrow transplant. No pharmaco-genetic assays were done and it's a very small sample size. This observational study revealed a better efficacy and tolerability of this dosing regimen in Indian Haplo-identical patients with a considerable response without compromising blood counts. The results are looking more promising to conduct this study in a bigger scale to benefit our patients from resource limited settings. Reference Zhao Y, Shi J, Luo Y, Gao F, Tan Y, Lai X, Yu J, Wei G, Huang H. Calcineurin Inhibitors Replacement by Ruxolitinib as Graft-versus-Host Disease Prophylaxis for Patients after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2020 May;26(5):e128-e133. doi: 10.1016/j.bbmt.2020.01.012. Epub 2020 Jan 23. PMID: 31982545.

Systematic Identification of Autosomal and Y-Encoded Minor Histocompatibility Antigens Reveals Predictors of Chronic Gvhd and Candidate GVL Targets

At the core of the therapeutic effect of HLA-matched allogeneic hematopoietic cell transplantation (allo-HCT) is T cell alloreactivity against minor histocompatibility antigens (mHAgs), polymorphic peptides resulting from donor-recipient disparity at sites of single nucleotide gene polymorphisms (SNPs). Despite their crucial role in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD), only few mHAgs have been characterized to date. To systematically identify autosomal and Y-chromosome encoded HLA-I restricted mHAgs, we devised a computational pipeline based on: (i) comparison of whole exomes (WES) from paired donor-recipient DNA to define recipient-restricted exonic non-synonymous polymorphisms; and (ii) generation of expression filters by incorporating published single cell expression profiles from normal and malignant hematopoietic cells and GvHD target organs. For each GvHD tissue (skin, liver, GI, lung, oral mucosa and lacrimal gland), a large single cell database combining ≥1 independent datasets was created to cluster and annotate tissue-resident cell types. Cell-type specific genes were defined based on their total number of reads (CPM>5 in any cluster), thus creating an expression atlas capturing less frequent albeit biologically relevant cell types underestimated in bulk expression profiles. For GvL predictions, we built an AML-specific filter by defining AML-expressed genes from single cell and bulk data, and by subtracting genes with expression in non-hemopoietic tissues, per transcriptome and proteome GTEx databases. Candidate GvL/GvHD mHAgs prediction was performed by applying the HLAthena binding prediction tool on recipient-restricted SNPs expressed in GvL or GvHD tissues. To validate the pipeline predictive power, we used a panel of 95 HLA class I monoallelic lines generated from B721.221 cells, which we previously profiled by WES, RNASeq and immunopeptidomics. By assigning the B721.221 genome as surrogate 'HCT recipient’ and the reference hg19 genome as surrogate 'donor', we identified recipient-restricted SNPs, whose class I-restricted presentation we confirmed by mass spectrometry for a median of 5 (range 1-16) predicted epitopes/ allele. For 2 HLA-A0201 epitopes encompassing SNPs with an allelic frequency <0.001, we validated immunogenicity through stimulation of PBMCs from HLA-A0201 healthy donors (HDs) with corresponding synthetic peptides. For Y-encoded mHAgs, we predicted a median of 62 (range 24-107) epitopes/HLA-I allele from 9 genes expressed (>1 TPM) in ≥1 non germline tissue. Analysis of 12 male immunopeptidomes confirmed presentation of 3 known Y mHAgs and 26 novel predicted epitopes across 18 alleles. To estimate the fraction of immunogenic predicted binders, we tested all Y epitopes predicted across 3 common alleles (A0201, B1801, C0501). Of 215 Y peptides tested, 53 (~25%) elicited an antigen-specific T cell response in PBMCs from female HDs, as per dextramer-based detection of ≥0.2% CD8 cells. To test the prognostic potential of the mHAg load on cGvHD risk, we performed WES on 220 donor-recipient pairs treated with matched-related-donor allo-HCT for myeloid disease at DFCI between 2013-2020. Our logistic regression analysis used organ-specific NIH moderate/severe cGvHD as outcome; as covariates, we included tissue-specific mHAg load and standard HCT variables (disease type and prognostic risk, conditioning intensity, graft type, GvHD prophylaxis, female into male [F→M] transplant, relapse). The burden of lung-expressed mHAgs was correlated with lung GvHD occurrence (P=0.023). Liver GvHD was associated with F→M transplants (P=0.023). Subgroup analysis further showed liver GvHD to be correlated with the number of epitopes predicted from the RPS14Y gene (P=0.037). For identification of AML-specific mHAgs, a median of 31 (range 13-50) mHAgs/patient were predicted in our cohort from 269 genes preferentially expressed in AML, with a trend for a protective effect of their load against relapse (P=0.058). Of note, 39 SNPs generated putative mHAgs shared by >10 patients and covering 8 common HLA-I alleles in Caucasians, thereby representing potential targets for post-HCT immunotherapy. Overall, we report the generation of a robust analytic pipeline which enables the broadening of the repertoire of mHAgs available for donor selection and for predicting, monitoring or manipulating GvL and GvHD after allo-HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Analysis on the Outcomes of Children with Acute Leukemia (AL) Receiving an Alpha/Beta T and B-Cell Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation (TBdepl-haploHSCT)

Background: We previously reported (Locatelli et al., Blood 2017) that TBdepl-haploHSCT is a suitable and effective option for children with AL lacking an HLA-compatible donor and/or needing an urgent allograft. This type of transplant is characterized by a low incidence of both acute and chronic graft-versus-host disease (GvHD) and by low non-relapse mortality (NRM), translating into survival outcomes comparable to those of patients transplanted from an HLA-compatible donor. Here we report an update on a cohort of 213 children with AL of our study, with a minimum follow-up of 180 days after the allograft. Patients and methods: Between October 2010 and January 2022, 213 children with AL received TBdepl-haploHSCT from an HLA-partially matched relative at Ospedale Pediatrico Bambino Gesù in Rome, Italy. All patients were in morphological complete remission (CR) and were prepared to TBdepl-haploHSCT using a fully-myeloablative conditioning regimen including a combination of total body irradiation (TBI) and/or cytotoxic drugs. All patients received also anti-T-lymphocyte globulin (ATLG) before transplantation (12 mg/kg total dose, from days -5 to day -3) to modulate bi-directional donor/recipient alloreactivity and rituximab (200 mg/sqm) on day -1 to prevent post-transplantation EBV-induced lymphoproliferative disorders (PTLD). No patient received any post-transplant pharmacological GvHD prophylaxis. Data were analyzed as of July 15, 2022. Results: Table 1 reports details on characteristics of patients included in the analysis. The median follow-up of surviving patients is 47.6 months (range: 6 months - 11.7 years). Two hundred and eight patients (98% of the total number) engrafted with a median time to neutrophil and platelet recovery of 13 (range 9-24) and 11 (range 7-23) days, respectively. Only 5 patients experienced graft failure; all were rescued with a second allograft. Eleven out of the 213 patients (5%) died of transplant-related complications (4 because of idiopathic pneumonia, 2 each because of disseminated adenovirus infection and thrombotic microangiopathy and 1 each of cardiac insufficiency, combined CMV/rhinovirus pneumonia and sepsis from Pseudomonas aeruginosa), the 5-year cumulative incidence of NRM being 5.2% (95% CI, 2.8-8.8). Forty-four patients relapsed at a median time of 192 days (range 56-1711) after HSCT, the 5-year cumulative incidence of relapse being 22.7% (95% CI, 16.9-29.2). Cumulative incidence of grade II-III acute GvHD was 14.7% (95% CI 10.6-20.3). Three patients and 1 developed gut and liver GvHD, respectively, while for all other patients skin was the sole organ involved. Fourteen out of the 193 patients at risk developed chronic GvHD, in all cases of limited severity, the cumulative incidence of this complication being 8.1% (95% CI 4.8-13.3). The 10-year probability of overall and leukemia-free survival (LFS) were 75.4 (95% CI 68.6-80.9) and 71.6% (95% CI 64.4-77.6), respectively. In univariate analysis, disease status at transplantation (CR1 vs CR2 vs CR>3), use of TBI during the preparative regimen and age at transplant above the median value (9.5 years) were associated with better patient's outcome, mainly because of a reduced incidence of relapse. Notably, among TBI-based regimens, the use of thiotepa and fludarabine was associated with an improved DFS as compared to other combinations (82.4% vs 63.9%, p=0.01). In a multivariable model for LFS including also gender and type of disease, only TBI (hazard ratio (HR) 0.38 (95% CI, 0.17-0.85, p=0.01) and disease status at HSCT (HR 1.72 (95% CI, 1.05-2.79, p=0.02) remained statistically significant. The 10-year GvHD/relapse-free survival was 65.1% (95% CI 57.7-71.4). The median CD3+ cell count on day +30, +90, +180 and +360 were 140, 185, 533 and 1058 /mcl, respectively. Conclusions: TBdepl-haploHSCT is becoming a widespread haplo platform for pediatric patients affected by both malignant and non-malignant disorders. This cohort of homogeneously treated patients, the largest reported so far with a median follow-up of almost 4 years, confirm once more the effectiveness and safety of this approach. Furthermore, this analysis identified subgroups of patients (e.g., those in CR>3) for whom post-transplant strategies aimed at reducing the risk of relapse (the main cause of treatment failure) are desirable. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis

AbstractIntestinal epithelial cells (IECs) are implicated in the propagation of T-cell–mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell–recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell–produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.

Liver-Intestinal Involvement in Graft Versus Host Disease in Pediatric Hematopoietic Stem Cell Transplantation Patients: Ten Years of Experience in 2 Centers of Latin America.

Retrospective cohort study of pediatric patients with history of hematopoietic stem cell transplantation for diagnosis of GVHD with gastrointestinal (GI) or liver involvement, from 2 pediatric centers. Between 2007 and 2017, 57 pediatric patients presented with liver or intestinal GVHD; 74% with GI GVHD, 11% with liver GVHD, and 15% with liver-intestinal involvement. Diarrhea (96%) and abdominal pain (55%) were the most frequent symptoms. Endoscopies were performed in 88%, and 35% required a second procedure to confirm diagnosis. Normal-appearing mucosa was observed in 17% of upper GI endoscopies and in 29% of colonoscopies. Endoscopic pathological findings were observed mainly in colon (62%). There was greater severity on colonoscopic classification in those with liver-intestinal compromise than in those with GI compromise only. Overall mortality was 26%. GI and liver GVHD diagnosis may present serious complications. GI involvement tends to manifest early, so it is appropriate to suspect it in the first days after transplantation, unlike liver involvement, which occurs late when other organs are involved. We did not observe a direct relationship between endoscopic and histological classification. Both GI and liver involvement in GVHD could predict greater target organ involvement.

Hematopoietic Stem Cell Transplantation in Paroxysmal Nocturnal Hemoglobinuria

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematological disorder characterized by episodic intravascular hemolysis. Despite newer therapies such as eculizumab, hematopoietic stem cell transplantation (HSCT) remains the only curative therapy. MATERIALS AND METHODS: An observational analytical retrospective study was conducted comprising eight PNH patients who had undergone HSCT at our center. From January 2014 to December 2020, we performed HSCT in 8 PNH patients, 5 female and 3 male, with median age of 32 years (range: 15–38 years). RESULTS: Seven patients had pancytopenia, associated with marrow hypocellularity. One patient presented with a thrombotic episode. Seven had matched sibling donor (MSD) transplant and one underwent haploidentical transplant. The median time from diagnosis to transplant was 7 months (range: 1–38 months). All received reduced intensity conditioning (RIC): Flu-Bu-Cy-A TG for MSD transplants and Flu-A TG-Post Cy in haploidentical transplants. Median CD34+ stem cell dose was 5.5 × 106/kg (range 3.4–5.8 × 106/kg). All had successful engraftment. Acute graft versus host disease (GVHD) Grade I–III occurred in six patients. Chronic GVHD occurred in two patients. One patient succumbed to Grade III liver GVHD. Rest seven patients are alive till date and transfusion independent. The overall survival was 87.5% at a median of 26 months. CONCLUSIONS: HSCT is the only curative therapy for PNH. With the use of RIC, the outcomes of PNH patients can be improved. The incidence of GVHD is high with RIC regimens but can be managed with prompt immunosuppression.

Peritransplantation ruxolitinib administration is safe and effective in patients with myelofibrosis: a pilot open-label study

AbstractWe report results of our prospective pilot trial evaluating safety/feasibility of peritransplantation ruxolitinib for myelofibrosis treatment. Primary objectives were to determine safety and maximum tolerated dose (MTD) of ruxolitinib. Ruxolitinib was administered at 2 dose levels (DLs) of 5 and 10 mg twice daily, with fludarabine/melphalan conditioning regimen and tacrolimus/sirolimus graft-versus-host disease (GVHD) prophylaxis. We enrolled 6 and 12 patients at DL1 and DL2, respectively. Median age at transplantation was 65 years (range, 25-73). Per Dynamic International Prognostic Scoring System, 4 patients were high and 14 intermediate risk. Peripheral blood stem cells were graft source from matched sibling (n = 5) or unrelated (n = 13) donor. At each DL, 1 patient developed dose-limiting toxicities (DLTs): grade 3 cardiac and gastrointestinal with grade 4 pulmonary DLTs in DL1, and grade 3 kidney injury in DL2. All patients achieved engraftment. Grade 2 to 4 and 3 to 4 acute GVHD cumulative incidence was 17% (95% confidence interval [CI], 6-47) and 11% (95% CI, 3-41), respectively. Cumulative incidence of 1-year chronic GVHD was 42% (95% CI, 24-74). With 22.6-month (range, 6.2-25.8) median follow-up in surviving patients, 1-year overall and progression-free survival were 77% (95% CI, 50-91) and 71% (95% CI, 44-87), respectively. Causes of death (n = 4) were cardiac arrest, GVHD, respiratory failure, and refractory GVHD of liver. Our results show peritransplantation ruxolitinib is safe and well tolerated at MTD of 10 mg twice daily and associated with dose-dependent pharmacokinetic and cytokine profile. Early efficacy data are highly promising in high-risk older patients with myelofibrosis. This trial was registered at www.clinicaltrials.gov as #NCT02917096.

Severe Ocular Graft-Versus-Host Disease Successfully Treated with Amniotic Membrane Transplantation - Case Series

Ocular graft-versus-host disease (GVHD) has the potential to lead to serious vision impairment, restriction of daily activities and deterioration of quality of life of patients after allogeneic stem cell transplantation (allo-SCT). Amniotic membrane transplantation (AMT) is an established technique in the treatment of various diseases of the ocular surface. This method could provide new options in the management of otherwise disabling severe ocular GVHD.We report a case-series of four patients with severe ocular GVHD refractory to standard local and systemic therapy, successfully treated with AMT. First patient was a 26-year old male who underwent a related allo-SCT for lymphoblastic transformation of chronic myeloid leukemia (CML) and received three donor lymphocytes infusions (DLI) due to molecular relapse. Six months later he developed severe GVHD of the mouth and eye that gradually deteriorated, despite corticosteroid treatment and topical therapy, and finally led to corneal perforation. In this case AMT was used to successfully seal the corneal perforation and to avoid keratoplasty. Moreover, AMT led to a durable clinical improvement continuing for four years after the treatment without the need for systemic immunosuppression. The second patient was a 25-year old male, transplanted from an unrelated donor for a CML refractory to tyrosine kinase inhibitors, who received one DLI for mixed chimerism and consequently developed GVHD of the skin, liver, lungs and eyes. Ocular GVHD progressed despite local and triple systemic immunosuppressive treatment. In this case AMT was applied before severe corneal ulcerations developed and led to full clinical recovery. The third patient was a 32-year old female who underwent an unrelated myeloablative allo-SCT for myelofibrosis, complicated with acute liver GVHD and slow immune reconstitution. At day +150 she developed a disabling herpes keratitis and stomatitis which led to prolonged hospitalization and slow recovery. At day +280 her vision deteriorated again, this time with signs of severe ocular GVHD. We feared herpes reactivation and hesitated from increasing immunosuppression. With this rationale we decided to perform AMT which again led to significant clinical improvement. Finally, our fourth patient underwent unrelated allo-SCT in the age of 22 for high risk myelodysplastic syndrome complicated with toxic epidermal necrolysis (TEN) of the skin, mucosa and eye. In this case chronic GVHD of the eye developed eight months later and gradually progressed, partly due to patient's non-compliance with treatment. This time AMT was applied on two consecutive occasions resulting in a similarly impressive clinical effect. The latter two patients also had marked corneal vascularization possibly due to the preceding involvement of the eye with viral infection and TEN. This was efficiently treated with additional subconjunctival anti-VEGF injections. With a median follow-up of 15 months, all four patients remained clinically stable without recurrence of severe ocular GVHD.Amniotic membrane is rich in cytokines, growth factors and protease inhibitors and serves as a biological bandage that suppresses inflammation and promotes epithelialization. In our experience, beside acute healing of corneal ulcerations in severe ocular GVHD and preventing perforation, it has a durable effect and prevents GVHD recurrence. Moreover, with the use of AMT we can avoid systemic immunosuppression and decrease both the risk of infectious complications and recurrence of the primary malignancy in allo-SCT patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Successful Management of Treatment-Emergent Chronic Graft-Versus-Host Disease of the Liver Following Nivolumab for Relapsed Hodgkin's Lymphoma after Allogeneic Stem Cell Transplant

PD-1 inhibition has been shown to effectively treat relapsed Hodgkin's lymphoma after allogeneic stem cell transplant (AlloSCT) by augmenting the graft-versus-lymphoma immune response. While PD-1 blockade post-Allo SCT is associated with a high overall response rate, there is also a high rate of severe graft-versus-host disease (GVHD) following treatment (Blood 2017 130:221-228). Many of the reported fatalities in this patient population have been associated with new onset treatment-refractory GVHD. Interestingly, GVHD occurring in this situation commonly manifests in the liver and can have features of both acute and chronic GVHD. This unique complication raises questions about the most effective treatment strategy. We report the successful management of PD-1 inhibitor-associated liver GVHD in a 31-year-old patient with classic Hodgkin's lymphoma, mixed cellularity subtype, who received the PD-1 inhibitor nivolumab for relapsed disease following a matched sibling donor peripheral blood Allo-SCT. The original indication for Allo-SCT was chemosensitive disease relapse following autologous stem cell transplant. The conditioning regimen was reduced-intensity busulfan and fludarabine and GVHD prophylaxis was low dose methotrexate and tacrolimus. Approximately 180 days after Allo-SCT the patient developed extensive chronic GVHD (elevated liver transaminases and decreased FEV1) which was successfully treated with a short course of oral steroids. Positron emission tomography-computed tomography (PET-CT) scan 1 year after Allo-SCT showed recurrent disease above and below the diaphragm. Brentuximab was initiated, resulting in resolution of hypermetabolic lymphadenopathy, but treatment was stopped after the third dose due to a severe infusion reaction. Three months later, PET-CT revealed multiple foci of high metabolic activity suggesting relapse. Vorinostat and sirolimus were initiated, and remission was obtained for the third time after Allo-SCT while on this regimen. After five months of vorinostat and sirolimus, the patient developed a pulmonary infection and subsequent biopsy-proven disease relapse. The patient was started on single agent nivolumab 3 mg/kg. Approximately 30 days after infusion the patient developed painful sclerodermatous lesions on the shins and increasing liver transaminases (Figure 1). Further treatment with nivolumab was held and 1 mg/kg/day of prednisone-equivalent was initiated. After 1 week, no improvement in liver enzymes was observed and prednisone was increased to 2 mg/kg/day. Sirolimus and mycophenolate mofetil were added. Despite initial improvement, transaminases and bilirubin increased again and a liver biopsy on day 48 of therapy showed lymphocytic cholangitis, cholestasis, ductopenia, and portal-to-portal bridging fibrosis consistent with chronic GVHD. AST peaked at 488 U/L, ALT peaked at 1093 U/L, and total bilirubin peaked at 1.7 mg/dL. Prednisone was increased to 3 mg/kg/day and extracorporeal photopheresis and Jakafi were initiated. Liver transaminases steadily declined. Prednisone was slowly tapered and maintenance therapy with Jakafi, sirolimus, and monthly extracorporeal photopheresis has maintained remission without a subsequent GVHD flare. PET/CT six months after nivolumab showed no evidence of disease, and the patient remains in clinical remission more than eight months after treatment. This case study highlights several uncertainties in the management of GVHD following PD-1 blockade. Should patients receive higher doses of steroids upfront (> 1 mg/kg/day)? Should GVHD prophylaxis be used? How should second-line therapies be chosen and how quickly should they be added? The largest case series to date by Haverkos et al. reports a high rate of treatment resistant GVHD suggesting that rapid escalation of immunosuppression is needed. Overall, this case represents a successful management of a newly-recognized and severe form of GVHD that can occur following PD-1 blockade in Allo-SCT recipients. Given that nivolumab is one of the few effective treatment options for relapsed Hodgkin's lymphoma after Allo-SCT, effective strategies for managing GVHD after PD-1 inhibition are needed. [Display omitted] DisclosuresLin:Jazz Pharmaceuticals: Consultancy. Ganguly:Amgen: Other: Advisory Board; Seattle Genetics: Speakers Bureau.

Post-transplant cyclophosphamide limits reactive donor T cells and delays the development of graft-versus-host disease in a humanized mouse model.

Graft-versus-host disease (GVHD) is a major complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) that develops when donor T cells in the graft become reactive against the host. Post-transplant cyclophosphamide (PTCy) is increasingly used in mismatched allo-HSCT, but how PTCy impacts donor T cells and reduces GVHD is unclear. This study aimed to determine the effect of PTCy on reactive human donor T cells and GVHD development in a preclinical humanized mouse model. Immunodeficient NOD-scid-IL2Rγnull mice were injected intraperitoneally (i.p.) with 20×106 human peripheral blood mononuclear cells stained with carboxyfluorescein succinimidyl ester (CFSE) (day 0). Mice were subsequently injected (i.p.) with PTCy (33mgkg-1 ) (PTCy-mice) or saline (saline-mice) (days 3 and 4). Mice were assessed for T-cell depletion on day 6 and monitored for GVHD for up to 10weeks. Flow cytometric analysis of livers at day 6 revealed lower proportions of reactive (CFSElow ) human (h) CD3+ T cells in PTCy-mice compared with saline-mice. Over 10weeks, PTCy-mice showed reduced weight loss and clinical GVHD, with prolonged survival and reduced histological liver GVHD compared with saline-mice. PTCy-mice also demonstrated increased splenic hCD4+ :hCD8+ T-cell ratios and reduced splenic Tregs (hCD4+ hCD25+ hCD127lo ) compared with saline-mice. This study demonstrates that PTCy reduces GVHD in a preclinical humanized mouse model. This corresponded to depletion of reactive human donor T cells, but fewer human Tregs.

Graves’ Disease, a Late Complication of Chronic Graft vs Host Disease

Introduction: Graft-versus-host disease (GVHD), a complication of bone marrow transplant (BMT), occurs when the donor white blood cells attack the recipient’s host cells and can occur acutely or chronically several years post-transplant. It is very rare for chronic GVHD to cause hyperthyroidism due to Grave’s disease and thyrotoxicosis years after BMT. Hyperthyroidism after BMT is thought to occur by GVHD or by donor’s auto-reactive lymphocytes transferred to recipient, with majority of cases occurring with donors that have an underlying autoimmune thyroid condition. Case Report: We report a 62 year old male who presented with palpitations, tremors, sweating, weight loss, and anxiety for 3 weeks. Past medical history was significant for allogenic BMT due to AML 14 years ago, which was further complicated by GVHD of eye, liver and skin. Physical exam was negative for thyromegaly or thyroid tenderness. Initial work up showed TSH 0.03 (normal 0.4-5.0 MUI/l), free T4 3.32 (normal 0.6-1.2 ng/dl), TSI 194 % (normal <140 %). Ultrasound revealed a diffuse hypervascular thyroid gland with numerous avascular cystic areas in both lobes and increased homogenous, symmetrical uptake consistent with Graves’ disease was noted on radioactive iodine uptake scan. With clinical suspicion of GVHD leading to Graves’ disease with subsequent thyrotoxicosis, he was started on methimazole. However, due to persistent increase in transaminases, concern for agranulocytosis with methimazole, and risk of developing worsening GVHD of the skin or eye with radioactive iodine therapy, he underwent total thyroidectomy. His pathology showed bilateral lymphoepithelial lesions with florid follicular hyperplasia, marked monocytoid hyperplasia, and Germinal B cells positive for CD10 and negative for BCL2. Lymphoepithelial lesions can be seen in chronic lymphocytic thyroiditis due to persistent inflammation. Conclusion: This case raises the question on the etiology of thyroid nodules and Graves’ disease occurring after BMT. We believe that his pathology findings may be due to chronic GVHD. Hyperthyroidism after BMT is extremely rare, with only a few case reports documenting this phenomenon. We believe that our patient developed hyperthyroidism 14 years after BMT most likely as a sequela of chronic GVHD with underlying immune dysregulation leading to formation of TSI and thyroiditis due to cellular invasion. This suggest a multifactorial etiology of hyperthyroidism in patients with GVHD. However, more prospective studies are required to the explain etiology of hyperthyroidism in GVHD. Moreover, such patients should be closely monitored for development of thyroid dysfunction or thyroid nodules.

Long-Term Follow-Up After the Application of Mesenchymal Stromal Cells in Children and Adolescents with Steroid-Refractory Graft-Versus-Host Disease.

Steroid-refractory graft-versus-host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). Alternative treatment options are often insufficient. Several studies have proven the efficacy of mesenchymal stromal cells (MSCs) in the treatment of therapy-refractory acute GvHD in adult and pediatric patients. Long-term data in pediatric patients are scarce. In this retrospective analysis, a total of 25 patients with a median age of 10.6 years (range 0.6-22.1 years) who received bone marrow-derived MSCs after alloHSCT for the treatment of steroid-refractory III and IV GvHD were analyzed. The median observation period of the surviving patients was 9.3 years (1.3-12.7 years) after HSCT. Among the 25 patients, 10 (40.0%) died [relapse (n = 3), multiorgan failure (n = 6), cardiorespiratory failure (n = 1)] at median 0.5 years (0.2-2.3 years) after HSCT. Partial response and complete remission (PR, CR) of the GvHD were achieved in 76.0% and 24.0% of the patients, respectively. Transplant-related mortality was 0% in the patients who achieved CR after MSC treatment and 26.3% for those with PR. A median improvement by one intestinal or liver GvHD stage (range 1-4) could be achieved after MSC application. No potentially MSC-related long-term adverse effects, for example, secondary malignancy, were identified. In conclusion, the intravenous application of allogeneic MSCs was safe and proved effective for the treatment of steroid-refractory GvHD. However, larger, prospective, and randomized trials are needed to evaluate these findings.

Safety of Allogeneic Stem Cell Transplantation after PD-1 Blockade for Patients with Relapsed/Refractory Classical Hodgkin Lymphoma: Focus on Immune-Related Adverse Events

Introduction: Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a potentially curative option for patients with relapsed and refractory Hodgkin lymphoma (rrHL). However, there is a question of applicability of allo-HSCT for patients previously treated with immune checkpoint inhibitors (ICIs). Initial reports indicate that allo-HSCT in this setting may be associated with increased risk of early transplant-related toxicity, graft versus host disease (GVHD), immune-related adverse events. But subsequently some studies demonstrated acceptable rates of both acute GVHD (aGVHD) and chronic GVHD (cGVHD) after prophylaxis with posttransplantation cyclophosphamide (PTCy). The aim of this study was to define safety and toxicity of allo-HSCT after ICIs for patients with rrHL. Patients and methods: We conducted a retrospective analysis of allo-HSCT results in 23 adult patients with rrHL performed between 2017 and 2019 in RM Gorbacheva Research Institute, Pavlov University. All patients were treated with ICIs before the transplantation (single-agent nivolumab, n=13; nivolumab and brentuximab vedotin, n=5; nivolumab and chemotherapy, n=5). The median time from the last dose of ICIs to allo-HSCT was 83 days (range, 50-350 days) and the median number of cycles was 20 (range, 6-32). Objective response to PD-1 therapy before allo-HSCT was documented in 15 patients (65%) including CR (n=9, 39%) and PR (n=6, 26%). Five patients (22%) had stable disease/disease progression and 3 patients (13%) were transplanted in indeterminate response according to LYRIC criteria. Three (13%) patients had matched HLA-related siblings, 12 patients (52%) had unrelated donors and 8 patients (35%) had haploidentical donors. All patients received reduced-intensity conditioning regimen (fludarabine 30 mg/m2, bendamustine 130 mg /m2 per day for 3 days (FluBe)) and PTCy-based GvHD prophylaxis. Bone marrow and peripheral blood stem cells was the graft source in 14 (61%) and 9 patients (39%), respectively. All analyses were performed using R 3.6.1 software. Results: At the time of analysis, median follow-up was 14 months (range, 1-26). Engraftment rate was 87%. Two patients had primary graft failure and there was 1 early death due to severe cytokine release syndrome after haploidentical HSCT. The 1-year OS and EFS were 83% (95% CI, 58-93) and 74% (95% CI, 49-87) respectively, whereas the 1-year cumulative incidences of relapse and NRM were 13% (95% CI, 5-39) and 13% (95% CI, 5-38) respectively.Out of the 20 patients with engraftment 15 patients developed acute GVHD including severe (grade III-IV) in 9 patients. All patients had skin aGVHD (stages 1, 2, and 3), 3 patients had gastrointestinal GVHD (stages 2, 3, and 4) and 2 patients had liver GVHD (stages 1 and 2). Four patients with steroid-refractory aGVHD received single-agent ruxolitinib (n=2) or combination of ruxolitinib with extracorporeal photopheresis (ECP) and steroids (n=2). All patients achieved complete response. Ten patients had chronic GVHD including 6 patients with moderate or severe disease. Most commonly skin (90%), mucosa (60%), gastrointestinal tract (30%), liver (20%), lung (10%) and eyes (20%) were involved. Four patients with steroid-refractory cGVHD achieved CR receiving combined immunosuppressive therapy (ruxolitinib and steroids, n=2; combination of steroids, cyclosporine A and ECP, n=2). One patient with severe skin cGVHD (score 3) achieved PR on combination of steroids and ECP, another patient with a severe refractory cGVHD (skin score 3, mucosa score 2 and lungs score 1) achieved stabilization only with third line of therapy (combination of ruxolitinib and imatinib). No cases of GVHD-related mortality were observed. There were no other immune-related adverse events. Conclusions: Our study showed the trend to higher incidence of aGVHD and cGHVD including steroid refractory form after ICIs, however this did not lead to GVHD-related mortality. Introduction of target agents for srGVHD might ameliorate GVHD-related mortality and morbidity in rrHL patients after ICIs. The optimal timing of allo-HSCT and regimen of GVHD prophylaxis are likely to be important in the successful outcome of the transplantation. Disclosures No relevant conflicts of interest to declare.

Severe Hypercholesterolemia Associated with Steroid-Refractory Acute Liver GVHD: Unusual Complication of Allogeneic Hematopoietic Cell Transplantation

Severe hypercholesterolemia is an uncommon complication of allogenic hematopoietic cell transplantation (HCT). Treatment options for hypercholesterolemia due to liver graft-versus-host disease (GVHD) are limited because many antilipidemic medications are known to worsen hepatic functions. We report our experience on a case of a 38-year-old male with Philadelphia chromosome positive acute lymphoblastic leukemia presenting with steroid-refractory hepatic and lower gastrointestinal acute GVHD after matched sibling donor peripheral blood myeloablative HCT who developed severe hypercholesterolemia (>1,000mg/dl). The patient was effectively treated with extracorporeal photopheresis for GVHD and severe hypercholesterolemia resolved after weeks of therapy with lipoprotein apheresis.

Profile of Hepatobiliary Dysfunction in Hematopoietic Stem Cell Transplant Recipients – An Indian Perspective

Hematopoietic stem cell transplantation (HSCT) is an established curative modality for various hematological malignancies and other diseases. Hepatobiliary dysfunction and subsequent sequelae constitute a common cause of morbidity and mortality in post-transplant scenario. However, data among Indian HSCT recipients is lacking. One hundred and one HSCT recipients (37 prospective and 64 retrospective) were followed up for hepatobiliary dysfunction in the post-transplant period. The causes for hepatobiliary dysfunction were categorized as sinusoidal obstruction syndrome (SOS), formerly known as veno-occlusive disease (VOD); acute and chronic graft-versus- host disease (GVHD); drug-induced liver injury (DILI); viral infections and miscellaneous causes including bacterial, fungal and unknown causes based on clinical and laboratory evidence. Among the 101 transplants, 56.44% (n=57) were allogenic transplants, and 43.56% (n=44) were autologous transplants. Hepatobiliary dysfunction was observed among 71 (70.30%) patients in first 30days and overall, among 78 (77.23%) patients. Incidence of hepatobiliary dysfunction was higher among allogenic transplant patients compared to autologous transplants (91.23% vs. 59.09%, p<0.001). The most common cause of hepatobiliary dysfunction reported was Drug-induced liver injury (DILI). In most cases, however, hepatobiliary dysfunction was multifactorial. Sinusoidal obstruction syndrome (15.79%), acute liver GVHD (31.58%), chronic liver GVHD (33.33%) and viral infection/reactivation (26.32%) were reported only in allogenic transplant patients. 15 (14.85%) patients died of which 14 patients had hepatobiliary dysfunction, commonest cause being infections. Our study reported a higher incidence of hepatobiliary dysfunction among Indian population post HSCT and was associated with significant mortality. In majority of the cases, the cause is multifactorial and pose a diagnostic dilemma and challenges in therapy.