Intestinal Transplant-Associated Thrombotic Microangiopathy: Histopathological Review. a Single Center Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3385-3385
Author(s):  
Javier Checa ◽  
Óscar Javier Blanco Núñez ◽  
Estefania Pérez-López ◽  
Mónica Cabrero ◽  
Ana A. Martín ◽  
...  
Keyword(s):  
Stem Cell ◽  
Endothelial Cell ◽  
Thrombotic Microangiopathy ◽  
Conflicts Of Interest ◽  
Endothelial Injury ◽  
Cell Swelling ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Pathological Review ◽  
Grade Iii

Abstract INTRODUCTION Transplant-associated thrombotic microangiopathy (TMA) is a severe complication after allogeneic stem cell transplantation (ASCT) due to endothelial injury caused by many factors such Calcineurin-inhibitors. In most severe cases, TMA could affect different organs. Intestinal TMA could be fatal and missdiagnosed in many patients. Clinical and pathological criteria to differentiate from intestinal GVHD are needed in order to distinguish both entities with different therapeutical approach. The aim of this study was to review pathological TMA features in patients diagnosed of systemic TMA . PATIENTS AND METHODS We analyzed the incidence of TMA in 527 pts who underwent ASCT in our institution between jan-2010 and apr-2018. Patients were identified if they had TMA according to probable TMA criteria by Ho. We do a pathological review in 96 samples from 18 of 42 patients in whom an endoscopy have been performed after the diagnosis of the TMA; endoscopy have been performed between 30 days before and 60 days after diagnosis of TMA for initial clinical diagnosis of GVHD. Review was performed by a pathologist expert. He examined the biopsies in search of features of GVHD, TMA or viral infection. Diagnosis of GVHD was stablished according to Mcdonald and Sales criteria, intestinal TMA diagnosis was perfomed by the 8 criteria summarized by Warren et al (perivascular mucosal hemorrhage, endothelial cell swelling, endothelial cell separation, intraluminal schistocytes, fibrin or microthrombi, loss of glands and mucosal denudation). RESULTS Baseline/transplant characteristics of patients with TMA are shown in table 1, TMA data in 2 and review hystological features of biopsies in 3. 45 (8.5%) were diagnosed of TMA with a median time from transplant of 75 days. Median age was 49 (19-69). Prophylaxis of GVHD was: Calcineurin inhibitor-MTX in 16 (35.5%), Tacrolimus-Sirolimus in 21 (46.6%), Tacrólimus-MMF and Cyclophosphamide in 8 (17.6%). 42 (93%) had prior or simultaneous acute GVHD, half of them grade III-IV, and 80% with gastrointestinal GVHD. 42% had elevated levels of tacrolimus and 13.6% elevated levels of sirolimus, one week before the diagnosis of TMA. Gastrointestinal MAT have been reported only in 5 patients (28%) at diagnosis whereas when review based on Warren criteria was performed, in 16 patients (89%) the pathologist found at least 1 of the criteria of endothelial damage and 50 % of the patients met 3 or more Warren criteria. The most frequent features were endothelial cell swelling (13 patients, 73 %) and perivascular mucosal hemorrhage (12 patients, 66.7%). In 3 biopsies which we perfomed the inmunochemistry of C4d, an activation of classic way of complement biomarker, it was positive. 4 of the 18 patients (22.2%) presented refractory-hypertension and 3 of them (26.6%) more than 30 mg/d Lof proteinuria, both suggested of poor prognosis. Regarding GVHD, it was founded in 72% at diagnosis and in all patients (18) at pathological review. 13 had grade I, 1 grade II, 1 grade III and 3 histological grade IV). With a median follow-up of 5 months (2-25) 25 of the 45 (56%) are dead. 6 of the deaths (24%) were related to TMA (1 due to TMA, 3 due to TMA+GVHD, 2 due to TMA+infection). Other causes of death were progression (4), GVHD+Infection (7), GVHD (3), infection (2), sinusoidal obstruction síndrome (1) and other causes (2). CONCLUSION TMA is a frequent complication, related with GVHD and underdiagnosed frequently. Only 5 of 18 patients were diagnosed of gastrointestinal TMA. In our study, we found that most of our patients had endotelial damage in the gastrointestinal biopsy pathological reviews. Although histological criteria of GVHD were present at review, in most of them it was only grade I; it contrasts with the severe clinical features. That lack of correlation would suggest that TMA and not GVHD is the main feature. Management of TMA and GVHD are different. To stress an appropiate diagnosis in gastrointestinal TMA is needed in order to offer the patients the best approach. REFERENCES Warren et al. A Complete Histologic Approach to Gastrointestinal Biopsy From Hematopoietic Stem Cell Transplant Patients With Evidence of Transplant-Associated Gastrointestinal Thrombotic Microangiopathy. Arch Pathol Lab Med.2017 Nov;141(11):1558-1566. Jodele S et al. A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29(3):191-204. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Complete Histologic Approach to Gastrointestinal Biopsy From Hematopoietic Stem Cell Transplant Patients With Evidence of Transplant-Associated Gastrointestinal Thrombotic Microangiopathy

2017 ◽  
Vol 141 (11) ◽  
pp. 1558-1566 ◽  
Author(s):  
Mikako Warren ◽  
Sonata Jodele ◽  
Christopher Dandoy ◽  
Kasiani C. Myers ◽  
Gregory Wallace ◽  
...  
Keyword(s):  
Stem Cell ◽  
Endothelial Cell ◽  
Hematopoietic Stem Cell ◽  
Thrombotic Microangiopathy ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Swelling ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Transplant Patients

Context.— Transplant-associated thrombotic microangiopathy is a serious complication of hematopoietic stem cell transplant that may progress to multi-organ dysfunction. Transplant-associated thrombotic microangiopathy may involve the intestinal vasculature (intestinal transplant-associated thrombotic microangiopathy [iTMA]), causing patients to experience debilitating symptoms of ischemic colitis, including disproportionately severe abdominal pain and gastrointestinal bleeding, requiring heavy narcotic use and frequent transfusion support. Pathophysiology remains poorly investigated but may include endothelial damage mediated by inflammatory markers and the complement system. Endoscopy of hematopoietic stem cell transplant patients often produces biopsy samples, in which mucosal lamina propria capillaries are sufficient for an evaluation of iTMA features. Objective.— To provide a detailed review of histologic features of iTMA. Data Sources.— We conducted a systematic review of studies assessing histologic features of iTMA. Studies were identified by PubMed search and included a cohort study performed by our group. Conclusions.— The histologic hallmark of iTMA is endothelial cell injury that leads to hemorrhage and thrombosis of the capillaries. Histologic features include endothelial cell swelling, endothelial cell separation, perivascular mucosal hemorrhage, intraluminal schistocytes, intraluminal fibrin, intraluminal microthrombi, loss of glands, and total denudation of mucosa. Identification of features consistent with iTMA has immediate implications for clinical management that could potentially improve outcome and survival.

scholarly journals Acute Kidney Injury and CKD Associated with Hematopoietic Stem Cell Transplantation

2019 ◽  
Vol 15 (2) ◽  
pp. 289-297 ◽  
Author(s):  
Amanda DeMauro Renaghan ◽  
Edgar A. Jaimes ◽  
Jolanta Malyszko ◽  
Mark A. Perazella ◽  
Ben Sprangers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Thrombotic Microangiopathy ◽  
Kidney Injury ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Wide Range

Hematopoietic stem cell transplantation is a life-saving therapy for many patients with cancer, as well as patients with some nonmalignant hematologic disorders, such as aplastic anemia, sickle cell disease, and certain congenital immune deficiencies. Kidney injury directly associated with stem cell transplantation includes a wide range of structural and functional abnormalities, which may be vascular (hypertension, thrombotic microangiopathy), glomerular (albuminuria, nephrotic glomerulopathies), and/or tubulointerstitial. AKI occurs commonly after stem cell transplant, affecting 10%–73% of patients. The cause is often multifactorial and can include sepsis, nephrotoxic medications, marrow infusion syndrome, hepatic sinusoidal obstruction syndrome, thrombotic microangiopathy, infections, and graft versus host disease. The risk of post-transplant kidney injury varies depending on patient characteristics, type of transplant (allogeneic versus autologous), and choice of chemotherapeutic conditioning regimen (myeloablative versus nonmyeloablative). Importantly, AKI is associated with substantial morbidity, including the need for KRT in approximately 5% of patients and the development of CKD in up to 60% of transplant recipients. AKI has been associated universally with higher all-cause and nonrelapse mortality regardless of transplant type, and studies have consistently shown extremely high (>80%) mortality rates in those patients requiring acute dialysis. Accordingly, prevention, early recognition, and prompt treatment of kidney injury are essential to improving kidney and patient outcomes after hematopoietic stem cell transplantation, and for realizing the full potential of this therapy.

Impact of Rapid Lymphocyte and Monocyte Recovery on Overall Survival Post-Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with Fludarabine/Melphalan Conditioning

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3040-3040
Author(s):  
Lori DeCook ◽  
Mary Thoma ◽  
Tanya Huneke ◽  
Nicole Johnson ◽  
Robert Wiegand ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Leukemia ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Positive Impact ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Absolute Lymphocyte Counts ◽  
Complete Blood Counts

Abstract Abstract 3040 We have previously shown that both lymphocyte and monocyte recovery are strongly associated with improved survival post-myeloablative allogeneic hematopoietic stem cell transplant for acute leukemia (Thoma et al, Biology of Blood and Marrow Transplantation, in press). We hypothesized that rapid lymphocyte and monocyte recovery would have a similarly positive impact on overall survival in reduced intensity conditioning (RIC) HSCT with fludarabine/melphalan. To test our hypothesis, we analyzed 118 consecutive patients who underwent allogeneic HSCT with fludarabine/melphalan conditioning for AML (n=49) and MDS/MPN (n=38), ALL (n=7) and other lymphoid malignancies (n=24) at our institution from 2001–2010. The absolute lymphocyte counts and monocyte counts (ALC and AMC, respectively) derived from routine complete blood counts were determined longitudinally at days +15, +30, +60, +100 and correlated with clinical outcomes. At the day +30 time point, both ALC and AMC > 0.3 × 10(9) cells/L were strongly associated with improved survival (OS 29.6 months vs. 5.4 months, p=0.006 and 25.3 months vs. 5.1 months, p=0.01 respectively), a pattern that continued through the day +100 evaluation. Multivariate analysis including age, CD34+ cell dose, unrelated vs. related HSCT, presence of aGVHD, remission status, and longitudinal hematologic parameters revealed that day +100 ALC (RR 0.21, 95% CI 0.07–0.66, p= 0.0096) and day +100 AMC (RR 0.41, 95% CI 0.2–0.9, p=0.047) were the only independent predictors of survival in the model. Pairwise correlations showed moderate negative associations between aGVHD and day +60 and day +100 ALC and AMC. To further explore whether any inherent patterns in the timing of lymphocyte and monocyte recovery had prognostic value post-HSCT, we performed unsupervised hierarchical clustering on the longitudinal hematopoietic parameters studied in this cohort and identified four clusters of patients, clusters A-D. Patient clusters A and C both demonstrated improved ALC and AMC recovery at the day +60 and day +100 time points and had significantly improved OS compared with clusters B and D (not reached for A and C vs. 54.9 and 22.3 months, respectively, p<0.001). No patient in cluster D had a day +100 AMC > 0.3 × 10(9) cells/L, and these patients experienced more acute GVHD (p=0.006) and relapse (8 of 14 patients, p=0.002) compared with clusters A, B, and C (p=0.002). 29 patients who were unable to be clustered with this algorithm, predominantly due to early toxic deaths, had a median survival of 6 months. Consistent with previous observations in our myeloablative cohort, both lymphocyte and monocyte recovery are predictive of overall survival post-RIC HSCT. However, compared to the myeloablative cohort, monocyte recovery in this series appears slightly less strongly associated with survival. Our results also extend the observation of improved survival of ALC and AMC recovery post-HSCT to diseases beyond acute leukemia. Disclosures: No relevant conflicts of interest to declare.

Prognostic Factors and Outcomes in Allogeneic Hematopoietic Stem Cell Transplant Vs. Non-Transplant Chronic Lymphocytic Leukemia (CLL) Patients: A Comparative Analysis with the Leukemia/BMT Program of British Columbia (BC) and the BC Provincial CLL Database

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2549-2549 ◽  
Author(s):  
Sebastian J. Swic ◽  
Alexander G. T. MacPhail ◽  
Chinmay B. Dalal ◽  
Steven J.T. Huang ◽  
Alina S. Gerrie ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Early Recognition ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Long Term Outcome

Abstract Background: Chronic Lymphocytic Leukemia (CLL) patients (pts) have significant (sig) heterogeneity; survival ranges from decades to <5 years (yrs). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is promising treatment (tx) for high-risk pts. Ideally, predictive (pred) tools would allow clinicians to recognize such pts early, permitting transplant performance to maximize benefit and minimize procedure associated risk. Factors with significant (sig) pred capacity are not, however, entirely clarified. Moreover, limited studies compare CLL pts who have/have not received HSCT in terms of differences (diff) in characteristics (char) at diagnosis (dx), population (pop) composition and outcomes. This study evaluates pred factors for outcomes post allo-HSCT, and compares dx char between (bn) tx CLL pts who did /did not receive HSCT by evaluating a large pop-based CLL cohort (n= 1044) from the BC Provincial CLL Database (BCPCD). Methods: 102 CLL pts (71M, 31F) had consecutive allo-HSCT (01-91 to 03-13, L/BMT Program of BC). Median (med) age (range) at dx:HSCT was 50 (26-65):57 (32-68) yrs; med interval dx to HSCT 5.8 yrs (0.5 to 29). Most pts (78, 76%) received non-ablative therapy; (n=61 [60%] reduced-intensity fludarabine /busulfan [flu/bu] based [RIC], n=17 [17%] non-myeloablative flu-cyclophosphamide based [NMA]); 24 pts had myeloablative (MA) conditioning (CON). Donor status was 50% unrelated (UD) (51UD:51RD); 73M, 28 F. Results: With median (med) follow up (FU) (range) post allo-HSCT of 2 yrs (0.5-18); post dx of 9 yrs (1-38), 67 (50%) pts survive. 70 (69%) achieved CR post-HSCT a med of 187 (28-1274) days (d). 27 had CLL PROG a med of 339 (25-4367) d; 18 of 27 (67%) survive a med of 3 (0.5-18) yrs post HSCT. Factors pred OS post HSCT (KM p=; UVA HR=) (p<0.05) were: pre-HSCT FISH deletion 17p (del 17p) (0.005; 2.9), Dohner rank (0.02), HSCT specific comorbidity index (CoI) >3 vs. 0-2 (0.04; 2.5), HLA mismatched (MM) donor (0.03;2.3), pre-HSCT tx with alemtuzumab (alem) (0.005;3.0), CON (MA vs NMA or RIC) (0.046; 3.0), acute (A) graft vs host disease (GVHD) grade (g) 3-4 vs 0-2. (<0.001; 4.5), dn chim <90% (0.001; 5.2), abn FISH not clear post-HSCT (0.009; 2.6), yr of HSCT (pre- vs post-2010) (0.03; 3.13) and lack of CR post HSCT (<0.001; 10.5).The following sig pred for (OR; p=): >90% dn chim: no B symptoms at dx (2.5; 0.004), CON (RIC vs. NMA, (2.6; 0.006); clear FISH abn post-HSCT: CR post-HSCT (4.6; 0.004); CR post-HSCT: B symptoms at dx (0.4; 0.02), <=1 FISH abn (1.7; 0.045), rituximab (R) pre-HSCT (2.5; 0.001), clear FISH abn (2.5; 0.01), flu sensitivity (S) pre-HSCT (1.8; 0.03), S to last tx pre-HSCT (1.7; 0.03), CON (MA vs. RIC or NMA) (3.2; <0.001); PROG: Richter’s transformation ( Rich trans) pre-HSCT (3.5; 0.008), graft failure (3.3; 0.008), CoI >3 vs. 0-2 (6.9; 0.006), no R pre-HSCT (6.7; 0.01), CON (MA vs. NMA or RIC), (0.2; 0.03); NRM: pre-HSCT alem (2.7; 0.03), CoI >3 vs. 0-2 (2.7; 0.049), HLA MM (2.8; 0.01), CON (MA vs. rest) (3.0; 0.007), AGVHD g 3-4 vs. 0-2 (5.9; <0.001), FISH abn not clear (2.6; 0.04), and no CR (6.5; <0.001). Comparison bn allo-HSCT and BCPCD CLL pts showed sig diff at dx for Dohner FISH rank: more del 17p (23% vs.11%) and 11q (23% vs. 9%) in allo-HSCT pts (n=84 with pre-HSCT FISH); less +12 (13% vs. 17%), del 13q (24% vs.41%) or normal (22% vs 18%), p<0.001 than non-HSCT pts (n=952); Age at dx (med, range) was lower in HSCT (50, 26-65) vs non (62, 25-96), p<0.001; lymphocyte (lymph) count higher (14, 1-300 vs.11, 1-662, p=0.03), tx-free survival (TFS) from dx to 1st tx shorter at 0.75 (0-9.3) vs. 2.86 (0-20.6) yrs. Rich trans was more frequent in HSCT pts (8%) vs. non (3%), p=0.015.OS was sig better for HSCT pts (n=103) (med 17.6, SE 4.5, CI 95% 8.8-26) compared to non (n=494) (med 14.4, SE 1.1, CI 95% 12.1-16.6) (p=0.03). Conclusion: CLL allo-HSCT pts have sig diff than non including higher lymph at dx, shorter time to 1st tx, and higher risk FISH abn. 17p del remains high-risk with allo-HSCT. Pre-HSCT R increased post HSCT CR. Strategies to optimize post-HSCT CR and dn chim are important; these milestones are crucial to best outcome. PROG post-HSCT does not confer worse OS; rescue strategies are successful and deserve further study. Comparison of this large allo HSCT and pop-based BPCDB cohort indicate improved OS for allo-HSCT tx CLL pts vs. other, with a survival plateau. This data indicates early recognition of high-risk CLL patients for HSCT is likely to yield best long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Thrombotic Microangiopathy with Tacrolimus/Sirolimus-Based GVHD Prophylaxis Regimen in Patients Undergoing Hematopoietic Stem Cell Transplant from a Matched Unrelated Donor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 797-797 ◽  
Author(s):  
Tam Khuu ◽  
Sepideh Shayani ◽  
Joycelynne Palmer ◽  
Roberto Rodriguez ◽  
Pablo Miguel Parker ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Thrombotic Microangiopathy ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Increased Risk

Abstract Thrombotic microangiopathy (TMA) is a multifactorial complication of related and unrelated allogeneic hematopoietic stem cell transplant (allo-HSCT). The true incidence of TMA is difficult to estimate due to lack of agreement on a single definition. Diagnosis is often complicated by multiple potential etiologies for the clinical findings. Sirolimus (SIR), an inhibitor of mammalian target of Rapamycin (mTOR), is a novel immunosuppressive agent that works synergistically with calcineurin inhibitors (CNI) to prevent graft-versus-host disease (GVHD) in allo-HSCT. Recently, the addition of SIR to CNIs was reported to result in a higher than expected incidence (10.8%) of TMA (Cutler et al. BBMT2005; 11:551–7). We evaluated the incidence and risk factors for TMA in a cohort of patients undergoing matched unrelated (MUD) HSCT using SIR combined with tacrolimus (TAC) and mini-methotrexate for GVHD prophylaxis at City of Hope. TMA was defined as SCr increase of ≥ 50% above baseline, LDH twice the institutional upper normal limit, presence of schistocytes or persistent presence of nucleated red blood cells, and prolonged or progressive thrombocytopenia (platelets <50 × 109/L or ≥ 50% decrease from previous count). A case series of 47 MUD-HSCT patients were included in this retrospective chart review study. The median age was 50 years (range: 19–67); (male/female: 28/19). Conditioning regimens consisted of fludarabine/melphalan (65%) and FTBI combined with cyclophosphamide or etoposide (35%). Diagnoses included ALL (32%), AML (25%), NHL (15%), MDS (15%), MPD (9%), CML (2%), CLL (2%). Twenty-six patients (55%) had a 10/10 matched (HLA-A, B, C, DRB1, and DQB1) donor by high-resolution on typing. The median follow up for the 30 surviving patients is 14.5 months (2.8–26). The one-year probabilities of overall survival and non-relapse mortality (NRM) were 61% and 19%, respectively. Grade II-IV acute GVHD (aGVHD) was reported in 60% of all patients (grade III-IV: 25%). Thirteen (28%) patients met the above diagnostic criteria for TMA. In addition, we included two patients who did not meet the criteria due to missing tests but were clinically diagnosed with TMA by independent attending physicians, resulting in the total incidence of 32% (15/47). Four of the 15 patients met the criteria for TMA as a result of ongoing multi-organ failure secondary to other causes. The median time to TMA onset was five weeks (2–20 weeks). Most cases (93%) occurred within the first 100 days post-HSCT. Thirteen patients developed both TMA and aGVHD, in which the majority of patients (70%) developed TMA after a diagnosis of aGVHD had been made. Initial treatments for TMA included holding TAC (33%), holding SIR (20%), holding or adjusting doses (27% and 20%, respectively) for both drugs. One patient underwent plasma exchange. Sixty percent of patients subsequently recovered from TMA as defined by normalization of laboratory values. Of the 17 expired patients, ten were diagnosed with TMA. Causes of death were as follows: for TMA cases, relapse mortality=3, NRM=7; for Non-TMA patients, relapse mortality=6, NRM=1. At the time of TMA diagnosis, the median TAC and SIR levels were 11.3 (0–18.8) and 7 (0–23.9) ng/ml, respectively, in contrast to the median TAC and SIR levels for non-TMA patients at 6.1 (p= 0.02) and 5.5 (p=0.13) ng/ml, respectively. To identify other possible risk factors for TMA, the following patient and treatment-related characteristics were examined: age, conditioning regimen, disease type, degree of HLA match, and exposure to triazole antifungals. Only higher tacrolimus levels (HR: 6.9, p<0.01) and aGVHD grades III-IV (HR: 3.5, p=0.02) were associated with an increased risk for TMA. In conclusion, TMA is common after MUD allo-HSCT using SIR-containing GVHD prophylaxis. The risk factors for TMA suggest that careful monitoring and adjustment of TAC/SIR dosages to avoid super-therapeutic levels is critical, particularly during ongoing GVHD.

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