Day-4 Lille Score Is a Good Prognostic Factor and Early Predictor in Assessing Therapy Response in Patients with Liver Cirrhosis and Severe Alcoholic Hepatitis

Lille score at Day 7 (LM7) helps to predict the outcome of patients with severe alcoholic hepatitis (sAH) undergoing corticotherapy. Several scores such as Maddrey’s discriminant function (MDF), MELD, ABIC, and GAHS are used for a 28-day mortality prognosis. Our study aimed to evaluate if the assessment of the Lille score at 4 days (LM4) is as useful as the Lille score at Day 7 (LM7) to predict response to corticosteroids and 28-day mortality and evaluate the utility of severity scores at admission for predicting the prognosis of patients with liver cirrhosis (LC) and severe alcoholic hepatitis (sAH). A retrospective study was performed, and all consecutive patients with AH and MDF > 32 without contraindications to corticosteroids were included. Prognostic scores were evaluated at admission, and 28-day mortality was assessed. Response to corticotherapy was assessed by LM4 and LM7. Results: A total of 55/103 patients with sAH (51.5%) had MDF > 32 and received corticosteroids. There was no difference between the proportion of patients with a responder LM4 versus LM7 (27% vs. 36%, p = 0.31). The mean value for LM4 was 0.64 ± 0.3 versus 0.60 ± 0.3 for LM7 (p = 0.48). Precisely 90.3% of patients were correctly identified as responders or not by LM4 compared with LM7. The best model for predicting 28-day mortality was composed of MELD and LM4/LM7, with an accuracy of 0.90 for both combinations. Conclusion: LM4 could be used instead of LM7 for predicting response to corticosteroid therapy in patients with sAH and LC, as well as 28-day mortality. Using LM4, we could avoid prolonged use of this therapy and its complications.

Short term outcome in severe alcoholic hepatitis patients treated with Methylprednisolone plus N acetylcysteine or Pentoxifylline plus N acetylcysteine

Introduction: Severe Alcoholic hepatitis (AH) is an acute form of alcohol induced liver injury. Often it present as fetal diseases with very high (30-50%) short term (28 days) mortality. This study was conducted from period May 2016 to July 2017 in Liver unit, Bir hospital. The main objective was to find out 28 days mortality in patients with severe alcoholic hepatitis who had Discriminant function (DF) ≥ 32. This was a prospective, comparative, randomized interventional hospital based study. Methodology: Hundred and ten diagnosed patients of severe alcoholic hepatitis who fulfilled the criteria were enrolled and randomized into two groups (odd number and even number). Group 1 received methylprednisolone and group 2 received pentoxifylline for 28 days. In both groups N acetylcysteine were added. Lille score was calculated in methylprednisolone group at day 7 and patients with score of ≤ 0.45 were continued methylprednisolone for total 28 days otherwise stopped. Data were recollected at day 28. They were compared in relation to survival, complications of drugs and causes of mortality. Results: Mean age of presentation were 40.21±10.5 yrs in methylprednisolone and 42.1±12.1 yrs in pentoxifylline group. In both groups complications were nausea, vomiting, bloating, anorexia and swelling of limb. However, hyperglycemia (16.4%) and renal impairment (9.1%) were more common in methylprednisolone group. Mortality rates were 34.5% in methylprednisolone and 37.8% in pentoxifylline group within 28 days. Common causes of death in both groups were hepatic encephalopathy, hepatorenal syndrome, sepsis or the cause was undetermined. Conclusion: Alcoholic hepatitis is common manifestation of alcoholic liver disease with high short term mortality in both the groups however adverse effects of drugs are more common in methylprednisolone groups.

Hepatologische Scores

Die folgenden hepatologischen Scores sind hilfreich dabei den Schweregrad für Lebererkrankungen einschätzen zu können, manche helfen bei der Diagnosestellung, andere können sogar dazu verwendet werden um eine Prognose für die weitere Entwicklung zu zeigen. Wir entschieden uns für 5 Scores welche im klinischen Alltag sehr nützlich sind: Child-Pugh-Turcotte-Score(CTP); MELD-Score, Score zur Diagnose einer Autoimmunhepatitis, den Mayo-Score für primär biliäre Zirrhose und den Lille-Score für alkoholische Hepatitis. In allen Scores werden klinische Merkmale und laborchemische Parameter verwendet um diese Aussagen treffen zu können.

Results of Phase II Clinical Trial MPD-RC 101: Allogeneic Hematopoietic Stem Cell Transplantation Conditioned with Fludarabine/Melphalan in Patients with Myelofibrosis

Abstract 1750 The Myeloproliferative Disorder-Research Consortium (MPD-RC) designed the first US prospective phase II study of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with primary myelofibrosis (PMF) or MF secondary to essential thrombocythemia (ET-MF) or polycythemia vera (PV-MF). Between May 2007 and March 2011, 66 patients were entered into the MPD-RC 101 study. Thirty-two patients received an allogeneic HSCT from a related and 34 patients from an unrelated donor. In the two groups diagnoses were: PMF: 44%, 74%; ET-MF: 47%, 12% and PV-MF: 9%, 15%, respectively. A reduced intensity regimen with fludarabine/melphalan (FluMel) ± ATG was used. Of 66 patients, 63 were at intermediate/high risk according to Lille score system and 3 patients were at low risk but had thrombocytopenia. Recipients of related and unrelated HSCT were comparable with respect to age (median: 54 vs 55 years), gender (M/F 19/13 vs 19/15), Lille score intermediate (63% vs 68%) or high risk (28% vs 32%) and time from diagnosis to transplant (median, range: 16, 1–247 vs 20, 2–341 months). At the time of transplant, 66% and 82% of patients in the related and unrelated cohorts had splenomegaly and 19% and 15% had previous splenectomy. Jak-2 V617F mutation was present in 38% and 50% and an abnormal karyotype was detected in 56% and 59% of patients with known status, respectively. Bone marrow stem cells were utilized in 19% of related and 9% of unrelated transplants, while in the remaining cases patients received peripheral blood stem cell (PBSC) grafts. Donor compatibility was assessed by molecular typing for HLA A, B, C, DRB1 and DQB1 antigens; inclusion criteria allowed enrollment with maximum 1 antigen mismatched donor. Thirty of 32 transplants (94%) in the related cohort and 25/36 (74%) in the unrelated cohort were fully matched. In transplants from related donor, engraftment of neutrophils and platelets occurred in 31/32 patients, One patient in this group experienced a secondary graft failure. In contrast, among patients in the unrelated group only 26/34 (76%) patients engrafted and of these 4 had a secondary graft failure post transplant. Median time to neutrophils > 0.5 × 109/L and platelets >20 × 109/L engraftment was: day 22 and day 28 in the related, and day 18 and day 28 in the unrelated cohort, respectively. Acute GVHD grade II-IV was observed in 37% related (grade III-IV: 12%) and in 42% unrelated transplants (grade III-IV: 21%). Based on the International Working Group criteria, in patients who were followed for at least 6 months there were 7 CR, 8 PR, and 11 CI among the 28 patients in the related group, and 5 CR, 1 PR, and 5 CI among the 16 patients in the unrelated group. After a median follow-up for survivors of 24 months, 25 patients (78%) in the related group are alive, 6 patients (18%) died for causes related to transplant (GVHD n=3, cardiac toxicity n=1, renal failure n=1, secondary cancer n=1) and 1 (3%) for progression of disease. In the unrelated group, 15 patients (44%) are alive at 12 months follow-up for survivors, 18 patients (53%) died for causes related to transplant and 1 patient (3%) due to relapse. Median survival time has not been reached in the related transplant group and is 7 months in the unrelated group (hazard ratio 4.2, 95% CI: 1.7–10.1, p<0.001). Survival in unrelated transplants was not associated with HLA matching, diagnosis, or the presence of Jak-2 mutation. In this prospective study a reduced intensity allogeneic HSCT with Flu/Mel regimen was very effective in patients with myelofibrosis transplanted from related donors. In unrelated transplants, a high rate of primary or secondary graft failure led to a high rate of transplant-related-mortality. For these patients a different conditioning regimen may be required. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) as a Curative Therapy in Primary and Secondary Myelofibrosis (MF): A 14-Year Period Oligocentric French Experience.

Background: MF patients (pts) with intermediate or high Lille score have a median survival from one to 2 years. After transformation into acute myeloid leukemia (AML), short-term survival is less than 5%. Until now, chemotherapy or other investigative drugs have not been reported to improve survival in pts with primary or secondary MF. Aim of the study: To describe the outcome of pts who underwent HSCT from 1994 to 2008 in 4 hematological French centers. Method: Thirty-nine pts with MF were identified. Overall survival (OS) and relapse free survival (RFS) were estimated by Kaplan-Meier method and cumulative incidence of non-relapse mortality (NRM) with relapse as a competing event, by Fine and Gray method (R Sofware). Patient and disease characteristics: Median age of pts at time of HSCT was 49 years (15–65). Twenty-seven pts had primary MF whereas 12 patients had MF secondary to polycythemia vera (PV) (n=7) or to essential thrombocythemia (ET) (n= 5). Among 25 pts with a cytogenetic analysis, 12 had clonal abnormalities. A JAK2 mutation was detected in 6 out of 22 tested patients (3/13 primitive MF, 1/2 MF secondary to TE and 2/3 MF secondary to PV). Treatment before transplantation mainly consisted of hydroxyurea or busulfan (26 pts). Before HSCT, 12 pts required platelet transfusions and 19 required blood transfusions. Twenty-three pts experienced a splenectomy in median 3 months before HSCT. Ten patients were transformed in AML before HSCT. Dupriez score was low in 9, intermediate in 16 and high in 14 pts at time of transplantation. Results: 25 pts received a HSCT from an HLA-identical sibling and all pts were transplanted with an HLA matched donor (3 9/10 HLA identities). Fifteen pts received a myeloablative conditioning regimen (MAC) and 24 received a fludarabine-based reduced intensity conditioning regimen (RIC). Graft-versus-Host disease (GVHD) prophylaxis consisted of cyclosporine plus mycophenolate in 21, cyclosporine plus methotrexate in 13 and cyclosporine alone in 5 pts. All but one pts engrafted in median 15 days (range:0–129) after transplantation. Median follow-up after HSCT was 729 days (79–1004). Thirty-one pts developed grade I-IV acute GVHD. Among 35 evaluable pts, 18 developed a chronic GVHD. Median time to discharge was shorter with RIC regimen (23 days) than with MAC regimen (46 days). Median OS was estimated at 4 years and 8 months. Three-year OS was 61% (95%Confidence Interval (CI): 47–80). 3-year RFS was 55% (41–75). 3-year NRM, was similar with RIC or MAC (32% (95%CI: 12–51) versus 20% (1–39). OS was not correlated to pre-transplantation Dupriez score (Low, OS: 57% (95%CI: 29–100)/Intermediate: 73% (95%CI: 53–99)/High: 56% (95%CI: 35–90)). Splenectomy, age, sex mismatch, CMV serology, conditioning regimen (RIC vs MAC) had no impact on outcome. Transformation into acute AML before HSCT was not a significant marker for poor OS (OS at 64%(95%CI: 48–85) versus 53% (95%CI: 18–28)). Patients who received platelet transfusions before HSCT had poorer OS: 25% (95%CI: 9–67) versus 78% (95%CI: 64–97), p &lt; 0.0001). Conclusion: In these high risk MF pts, median OS after HSCT is much better than reported with alternative treatment. The main risk factor for poor outcome is thrombocytopenia requiring platelet transfusion before transplantation whereas other usual risk factors have no more impact after HSCT.

High Blast Percentage, Chromosome 17 Abnormalities and Severe Pancytopenia Predict Death within Twelve Months in Patients with Myelofibrosis.

Existing prognostic models for myelofibrosis (MF) are based on complete blood count parameters and clinical symptoms at the time of initial presentation, with the most widely cited being the Lille score (Blood 88.1013). These models, however, are only applicable to patients at the time of initial diagnosis, and they do not identify the patients at imminent risk of death. In order to identify patients in advanced phase (AP) MF that may be candidates for intensified therapy, we reviewed the records of 371 MF patients for disease features that predict for survival less than twelve months. Median baseline characteristics (range): age 63 yrs (24–86); male 59%; post-PV or post-ET MF 21%; spleen 5cm (0–30); HB &lt;10g/dL or transfusion dependent (TD) 53%; abnormal cytogenetics 126/337 (37%). Patients presented at a median of 4 months (range, 0 to 296 months) from initial diagnosis; 6% were previously treated with alkylators or radiation, and 36% with hydroxyurea. Median follow-up was 46 months for survivors. Independent predictors of poor survival at initial presentation were: abnormal chromosome 17 (ABN17; p&lt;0.001); age (p&lt;0.001); hepatomegaly ≥5cm (p&lt;0.001); platelets &lt;100 (p&lt;0.001); HB &lt;10 or TD (p&lt;0.001); abnormal WCC (p=0.007); PB or BM blasts ≥10% (p=0.008); splenomegaly ≥20cm (p=0.02); and male gender (p=0.02). Factors significant on univariate analysis but not significant on multivariate modelling included primary vs secondary MF, other cytogenetic abnormalities, previous radiation / alkylator or erythropoietin exposure, monocytes ≥1×10^9/L, abnormal creatinine or bilirubin, and performance status. Three disease features were chosen as criteria for AP because of their association with median survival &lt;12 months: PB/BM blasts ≥10% (n=19, survival 10 months), ABN17 (n=9, survival 5 months) and severe cytopenia not related to therapy (PLT &lt;25 and WCC &lt;4.0, n=9, survival 8 months). These criteria were independent of existing prognostic models: among patients with a high-risk Lille score, median survival was significantly inferior for patients with AP criteria (n=19, 5 months) compared to those without (n=55, 24 months p&lt;0.0001). In order to validate these criteria, we followed the progress of 334 patients not in AP at presentation. During follow-up, 56 additional patients met AP criteria, and median survival from AP development were: PB/BM blasts ≥10% (n=38), 12 months; ABN17 (n=6), 6 months; severe cytopenia not related to therapy (n=12), 10 months. The actuarial risk of AP development was 23% at 4 years. Of the 93 patients in AP, blast phase (BP) occurred in 30 (32%), and a further 46 (49%) died without reaching BP. In contrast, BP occurred in only 9 of 278 (3%) of patients in chronic phase (p&lt;0.0001). Our observations indicate that PB/BM blasts ≥10%, ABN17 and severe cytopenia evolve during the natural history of primary or secondary MF and are associated with a high risk of blastic transformation or death from progressive disease. Recognition of such patients as AP is an important step in facilitating the development of high-risk intervention strategies.

Splenectomy in Patients with Chronic Myeloid Leukemia or Myeloproliferative Diseases: Outcomes, Complications and Prognostic Implications.

The results of splenectomy in 110 patients with myeloproliferative disorders (MPD) were analyzed to determine short-term outcome and complications, and long-term impact on AML transformation and survival. Thirty-one patients had CML in chronic(CP; n=10), accelerated(AP, n=10) or blast phase(BP, n=11); 60 myelofibrosis in CP(n=59) or BP(n=1); 8 CMML; and 11 other MPDs. Median characteristics (range): age 58 yrs (16–85), male 60%, time from diagnosis 6 months (0–187), 2 prior therapies (0–7), performance status 1 (0–3), B-symptoms 70%, transfusion-dependent 50%, spleen 15cm (0–30) below LCM. The number of indications for splenectomy was 1 in 44%, 2 in 40%, and ≥3 in 16%, with the most common indications being pain/ local symptoms (54%), anemia/ transfusion dependency (59%) and thrombocytopenia (39%). For patients with anemia/ transfusion-dependency, Hb improved ≥2g/dL &/or transfusion requirement decreased by half in 68% for a median of 13 months. For patients with thrombocytopenia, 66% improved platelet count by &gt;30×10^9/L for a median of 18 months. No patient had deterioration in Hb or Plt post-splenectomy not otherwise explained by disease or concomitant therapy. Complications occurred in 58% patients with the most common being thrombocytosis &gt;1000×10^9/L (17%), venous thrombosis (16%), pneumonia (10%), abdominal collection (9%), leucocytosis &gt;150×10^9/L (6%), painful hepatomegaly (4%) and bleeding (3%). Sites of thrombosis were: 10 portal vein, 3 Budd-Chiari, 3 DVT/PE, 2 splenic vein and 1 SVC obstruction; 2 patients had multiple thrombosis sites. Patients with baseline platelets ≥150×10^9/L were more likely to develop platelets &gt;1000×10^9/L postoperatively (39% v 6%, p&lt;0.001), who in turn were at an increased risk of venous thrombosis (32% v 13%, p=0.05). Median survival was 19 months: most patients died of progressive disease, with only six deaths attributable to surgery, and the occurrence of surgical complications had no impact on survival (p=0.45). In order to assess the impact of splenectomy on AML risk and survival of myelofibrosis patients, we compared outcomes between 53 study patients and 267 control (non-splenectomized) patients from the MD Anderson MPD database. Patient with features of pre-terminal disease (blasts ≥10%, abnormal chromosome 17 or severe cytopenia) were excluded from this analysis. In this comparison, splenectomized myelofibrosis patients experienced inferior survival (median 21 v 46 months, p&lt;0.001), with the difference remaining significant (HR 1.6 p=0.02) after accounting for age, cytogenetics, blast%, monocyte count and Lille score in a multivariate analysis. AML risk was also increased in splenectomized patients, but occurred in only a minority of patients (23% at 4 yrs, v 13% for controls, p=0.01), and splenectomy was not an independent factor for AML development after accounting for peripheral blood blast% (HR 1.3, p=0.008) and Lille score (HR 2.2 p=0.005) in multivariate analysis. The requirement of splenectomy for disease control is an independent predictor of poor outcome in patients with myelofibrosis.