The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg ( N = 223), IM 600 mg ( N = 171), IM 400 mg + AraC ( N = 172), and IM 400 mg + PegIFN-α2a ( N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.

In total, 279 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 10 years. Data were collected up to June 2018. We analyzed responses to treatment, relapses, survival, and the occurrence of second malignancies during follow-up. The median age was 59 years. In total, 208 patients (75%) were treated with purine analogs (PNAs), either cladribine (159) or pentosatin (49), as the first-line therapy. After a median follow-up of 127 months, the median overall survival was 27 years, and the median relapse-free survival (RFS) was 11 years. The cumulative 10-year relapse incidence was 39%. In patients receiving second-line therapy, the median RFS was 7 years. For the second-line therapy, using the same or another PNA was equivalent. We identified 68 second malignancies in 59 patients: 49 solid cancers and 19 hematological malignancies. The 10-year cumulative incidences of cancers, solid tumors, and hematological malignancies were 15%, 11%, and 5.0%, respectively, and the standardized incidence ratios were 2.22, 1.81, and 6.67, respectively. In multivariate analysis, PNA was not a risk factor for second malignancies. HCL patients have a good long-term prognosis. PNAs are the first-line treatment. HCL patients require long-term follow-up because of their relatively increased risk of second malignancies.

Introduction: Hairy-cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with a favorable outcome thanks to treatment with purine analogues (PNA) like cladribine and pentostatin. Here, we updated the French national retrospective cohort of HCL after 10 years of follow-up, in order to evaluate the risk of second cancers in these patients. Methods: Data were collected up to June 2018 through a questionnaire sent to the members of the Société Française d'Hématologie, and centralized in the cohort database. We described the second malignancies observed during the follow-up, distinguishing second 'solid' cancers from second hematological malignancies. Then, using a Fine and Gray model, we performed a multivariate analysis in order to identify second cancer risk factors. Finally, to evaluate the excess of cancers in our cohort in comparison with the French general population, we calculated the standardized incidence ratio (SIR). Results: 279 patients (pts) from 19 centers were included in our retrospective cohort. The median age was 59 years old (range 29-88). 21% had an infectious disease at diagnosis, 23% had a familial history of cancer and 11% a personal history of cancer before HCL diagnosis. The median number of lines of treatments was 1 (0-7). PNA (cladribine or pentostatin) were the first therapeutic choice in frontline (75% of pts) and at relapse (69%). With a median follow-up of 127 months (2-413), the median overall survival for the overall study population was 328 months (95% CI 299-357) and the median relapse-free survival (RFS) was 136 months (95% CI 109-163). Pts treated with cladribine or pentostatin in first line had a statistically significant better RFS than pts treated with 'other' treatments (log rank test, p < 0.001). The 10-year cumulative incidence of relapse was 39% (95% CI 33-46). Pts who received treatments other than PNA in first line had a higher risk of relapse (Gray's test, p < 0.001). For pts receiving PNA in first and second lines, there was no difference in outcomes between those who switched PNA and those who did not. In this cohort, we observed 68 second malignancies during the follow-up: 49 solid cancers (most prevalent: prostate and non-melanoma skin cancers) and 19 hematological malignancies (most prevalent: monoclonal gammopathy of undetermined significance (MGUS) and myelodysplastic syndromes (MDS)). The median onset of second cancer, second solid cancer and second hematological malignancy from HCL diagnosis was 81 months, 99 months and 78 months, respectively. The median age at diagnosis of cancer, solid cancer and hematological malignancy was 70, 69 and 77 years old, respectively. Considering death as a competing risk, the 10-year cumulative incidence of cancer, solid cancer and hematological malignancy was 15% (95% CI 11-19), 11% (95% CI 7.2-15), and 5.0% (95% CI 2.8-8.2), respectively. In multivariate analyses, IFN treatment was associated with a decreased risk for all cancers (Fine and Gray regression model, subdistribution Hazard Ratio (sdHR) 0.53 (95% CI 0.29-0.97); p = 0.038), a familial history of cancer was a risk factor for solid cancers (sdHR 2.12 (95% CI 1.15-3.91); p = 0.017), a personal history of cancer was a risk factor for hematological malignancies (sdHR 3.47 (95% CI 1.14-10.55); p = 0.028). Even after excluding non-melanoma skin cancers and MGUS, there was an excess of cancers (SIR = 2.22), solid cancers (SIR = 1.81) and hematological malignancies (SIR = 6.67). Conclusions: In this updated real-world retrospective cohort with a long follow-up and most pts treated with PNA, we highlighted the importance and the excess of second cancers in HCL patients, in particular hematological malignancies. Figure Disclosures Paillassa: Janssen: Other: Bibliography board with young hematologists. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Hermine:AB Science: Membership on an entity's Board of Directors or advisory committees. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support.

e20520 Background: Comprehensive geriatric assessment (CGA) helps therapeutic decision, predicts chemotherapy toxicities and early deaths in elderly patients treated for advanced cancer. CGA, performed at the time of oncologic therapeutic decision (initial CGA), has been progressively implemented in the Picardie region since 2008. In order to evaluate the clinical impact of initial CGA on survival of elderly cancer patients, we launched a retrospective multicentric collaborative study (IEGAC). Methods: Data from patients aged of 75 years or older and who received first line chemotherapy for advanced breast, ovary or colorectal cancer, from 2008 to 2012 were collected. Two groups were defined based on the implementation (group A) or not (group B) of initial CGA. Primary endpoint was overall survival (OS) from start of chemotherapy until patient’s death or last contact. Survival was calculed using Kaplan Meier method, log rank test used to comparison. Survival curves were adjusted with propensity score method, Cox model was built to explore relationship between survival and main explanatory variables. Results: 60 patients were includedin group A and 78 in group B. Mean age was 81 years in group A and 79 in group B (p = 0.002). With a median follow up of 89.2 months [95%CI: 44.6-not reached] median OS was not significantly different between group A (24.3 months, [95%CI: 21.4-30.4]) and B (29.3 months, [95%CI: 19.2-34.5]), HR = 0.94 (95%CI:0.61-1.43, p = 0.77). There was no difference of median OS between patients aged under 80 and over with initial CGA (HR = 0.69,95%CI:0.32-1.49;P = 0.35) or not (HR = 0.93,95%CI:0.51-1.69;P = 0.81) Conclusions: In this retrospective study, initial CGA did not have any impact on median OS of elderly cancer patients treated with chemotherapy. These results could be explained by a lack of power or selection bias inherent of any retrospective study, but they more probably reflect a huge improvement in the management of chemotherapy.

The CD3−CD4+ lymphoid variant of hypereosinophilic syndrome is characterized by hypereosinophilia and clonal circulating CD3−CD4+ T cells. Peripheral T-cell lymphoma has been described during this disease course, and we observed in our cohort of 23 patients 2 cases of angio-immunoblastic T-cell lymphoma. We focus here on histopathological (n=12 patients) and immunophenotypic (n=15) characteristics of CD3−CD4+ lymphoid variant of hypereosinophilic syndrome. Atypical CD4+ T cells lymphoid infiltrates were found in 10 of 12 CD3−CD4+ L-HES patients, in lymph nodes (n=4 of 4 patients), in skin (n=9 of 9) and other extra-nodal tissues (gut, lacrymal gland, synovium). Lymph nodes displayed infiltrates limited to the interfollicular areas or even an effacement of nodal architecture, associated with proliferation of arborizing high endothelial venules and increased follicular dendritic cell meshwork. Analysis of 2 fresh skin samples confirmed the presence of CD3−CD4+ T cells. Clonal T cells were detected in at least one tissue in 8 patients, including lymph nodes (n=4 of 4): the same clonal T cells were detected in blood and in at least one biopsy, with a maximum delay of 23 years between samples. In the majority of cases, circulating CD3−CD4+ T cells were CD2hi (n=9 of 14), CD5hi (n=12 of 14), and CD7−(n=4 of 14) or CD7low (n=10 of 14). Angio-immunoblastic T-cell lymphoma can also present with CD3−CD4+ T cells; despite other common histopathological and immunophenotypic features, CD10 expression and follicular helper T-cell markers were not detected in lymphoid variant of hypereosinophilic syndrome patients, except in both patients who developed angio-immunoblastic T-cell lymphoma, and only at T-cell lymphoma diagnosis. Taken together, persistence of tissular clonal T cells and histopathological features define CD3−CD4+ lymphoid variant of hypereosinophilic syndrome as a peripheral indolent clonal T-cell lymphoproliferative disorder, which should not be confused with angio-immunoblastic T-cell lymphoma.

The CD3-CD4+ aberrant T-cell phenotype is the most described in the lymphoid variant of hypereosinophilic syndrome (L-HES), a rare form of HES. Only a few cases have been reported, and data for these patients are scarce. To describe characteristics and outcome of CD3-CD4+ L-HES patients, we conducted a national multicentric retrospective study in the French Eosinophil Network. All patients who met the recent criteria of hypereosinophilia (HE) or HES and who had a persistent CD3-CD4+ T-cell subset on blood T-cell phenotyping were included. Clinical and laboratory data were retrospectively collected by chart review. CD3-CD4+ L-HES was diagnosed in 21 patients (13 females, median age 42 years [range, 5-75 yr]). Half (48%) had a history of atopic manifestations. Clinical manifestations were dermatologic (81%), superficial adenopathy (62%), rheumatologic (29%), gastrointestinal (24%), pulmonary (19%), neurologic (10%), and cardiovascular (5%). The median absolute CD3-CD4+ T-cell count was 0.35 G/L (range, 0.01-28.3), with a clonal TCR gamma delta rearrangement in 76% of patients. The mean follow-up duration after HES diagnosis was 6.9 +/- 5.1 years. All patients treated with oral corticosteroids (CS) (n = 18) obtained remission, but 16 required CS-sparing treatments. One patient had a T-cell lymphoma 8 years after diagnosis, and 3 deaths occurred during follow-up.In conclusion, clinical manifestations related to CD3-CD4+ T cell-associated L-HES are not limited to skin, and can involve all tissue or organs affected in other types of HE. Contrary to FIP1L1-PDGFRA chronic eosinophilic leukemia patients, CS are always effective in these patients, but CS-sparing treatments are frequently needed. The occurrence of T-cell lymphoma, although rare in our cohort, remains a major concern during follow-up.

The CD3-CD4+ aberrant T-cell phenotype is the most described in the lymphoid variant of hypereosinophilic syndrome (L-HES), a rare form of HES. Only a few cases have been reported, and data for these patients are scarce. To describe characteristics and outcome of CD3-CD4+ L-HES patients, we conducted a national multicentric retrospective study in the French Eosinophil Network. All patients who met the recent criteria of hypereosinophilia (HE) or HES and who had a persistent CD3-CD4+ T-cell subset on blood T-cell phenotyping were included. Clinical and laboratory data were retrospectively collected by chart review. CD3-CD4+ L-HES was diagnosed in 21 patients (13 females, median age 42 years [range, 5–75 yr]). Half (48%) had a history of atopic manifestations. Clinical manifestations were dermatologic (81%), superficial adenopathy (62%), rheumatologic (29%), gastrointestinal (24%), pulmonary (19%), neurologic (10%), and cardiovascular (5%). The median absolute CD3-CD4+ T-cell count was 0.35 G/L (range, 0.01–28.3), with a clonal TCRγδ rearrangement in 76% of patients. The mean follow-up duration after HES diagnosis was 6.9 ± 5.1 years. All patients treated with oral corticosteroids (CS) (n = 18) obtained remission, but 16 required CS-sparing treatments. One patient had a T-cell lymphoma 8 years after diagnosis, and 3 deaths occurred during follow-up. In conclusion, clinical manifestations related to CD3-CD4+ T cell-associated L-HES are not limited to skin, and can involve all tissue or organs affected in other types of HE. Contrary to FIP1L1-PDGFRA chronic eosinophilic leukemia patients, CS are always effective in these patients, but CS-sparing treatments are frequently needed. The occurrence of T-cell lymphoma, although rare in our cohort, remains a major concern during follow-up.

Abstract Abstract 280 Background: Two phase 2 studies have recently shown promising results of peg-IFNα-2a therapy in PV and essential thrombocythemia, including major efficacy, satisfactory tolerance, and significant molecular responses, renewing the interest for IFNα therapy in patients (pts) with MPN. However, no prospective study has assessed the long-term safety and efficacy of IFN therapy in those pts. We analyzed the long-term results of the PVN1 trial (www.clinicaltrials.gov #NCT00241241), a phase 2 study of peg-IFNα-2a therapy in PV, after a median follow-up (FU) of 6.4 years. Patients and methods: 40 PV pts were enrolled in the study between Sept 04 and Sept 05. 4 pts were not evaluable (1 inclusion criteria violation, 2 withdraws of consent, 1 allergic reaction at first injection). Median age was 50 yrs (range 22–65). Median time since diagnosis was 6 months (range 1–65). 9 pts (25%) had previously received hydroxyurea. 6 pts (17%) had a history of thrombosis. 7 pts (20%) had splenomegaly. Long-term analyses were performed in 34 patients in June 11 (2 pts lost to FU). Hematological, molecular and histological responses were assessed according to the European LeukemiaNet (ELN) criteria. Results: Median FU was 77.4 months (mos) (Q1−Q3: 72 – 81 mos) and median duration of peg-IFNα-2a therapy was 47.4 mos (Q1-Q3: 28 – 77 mos). Clinical-hematological efficacy: At last evaluation, 32/34 pts (94%) were in hematological response including 28/34 complete responses (CR) (82%) and 4 partial responses (PR), and 2 pts had relapsed. 14 pts (41%) were still treated with peg-IFNα-2a for a median time of 70 mos. During FU, 20 pts stopped IFN after having received the drug for a median time of 42 mos. Among them, 10 pts (29% of the total cohort) had stopped because of sustained hematological CR, 8 (23%) because of toxicity, and 2 (6%) at investigator's discretion. 13 (38% of the total cohort) of the 20 pts who stopped therapy did not received any other cytoreductive treatment after peg-IFNα-2a discontinuation, and 10/13 were still in hematological CR off-therapy at last evaluation after a mean observation period of 28+ mos (range 3+ – 64+ mos). During FU, PV relapsed in 3/13 pts who had stopped cytoreductive therapy after a mean time of 25 mos (range 6 – 37 mos). Peg-IFNα-2a was restarted in 2 of them and a second hematological CR was achieved. None of the patients experienced any vascular event during FU, when about 10 events would have been expected in this series of 34 PV pts followed for 77 mos (5.5% pts/year in the ECLAP study). Molecular and histological responses: Molecular response was assessed by measuring JAK2V617F allele burden in granulocytes (%V617F) in 29 pts with serial samples: a molecular response was achieved in 24 pts (83%) including 8 molecular CR (28%), and only 5 pts (17%) had no decrease in their %V617F. Mean %V617F was 47% (range 10 – 100%) at baseline, and 10% (range 0 – 45%) at 72 mos. 4 pts had a TET2 mutation: in none of them the TET2 mutant allele burden decreased during therapy although median decrease in %V617F in the same samples was 100% (Q1 – Q3: 75% – 100%). Bone marrow biopsies performed in some pts in hematological CR after discontinuation of peg-IFNα-2a found a normalized BM morphology fulfilling the ELN criteria for histological CR, and excluded an evolution to myelofibrosis as a cause for “apparent” remission. Toxicity: Peg-IFNα-2a was stopped because of adverse event in 8 pts (23%): fatigue in 2, depression in 1, grade 2 neuropathy in 1, arthralgia in 1, thyroiditis in 1, auto-antibodies in 1, liver enzyme elevation in 1 pt, respectively. Importantly, no unexpected adverse event was observed in spite of the very long-term use of peg-IFNα-2a (median of 45.5 mos). Conclusion: In this prospective phase 2 study of PV pts treated with peg-IFNα-2a after 6.4 years median FU, we recognized that: 1) 94% of pts were still in hematological response, including 82% CR; 2) 29% of pts could stop peg-IFNα-2a and remained in hematological response without further cytoreductive therapy after a median observation time of 28+ mos (up to 64+ mos); 3) major and sustained molecular response in %V617F was confirmed in 83% of patients, including 28% who achieved complete molecular response, while TET2 mutated clones appeared resistant to peg-IFNα-2a; 4) histological CR was also achieved in selected patients; 5) no vascular event was observed after 6.4 years median FU; 6) no new safety concern arose with prolonged utilization of peg-IFN alpha-2a. Disclosures: Off Label Use: Phase 2 study of pegylated-Interferon alpha-2a in polycythemia vera (off-label).

We report the clinical response and biological effects of treatment with rituximab and fludarabine (RF) in five patients with IgM anti-myelin-associated glycoprotein (MAG) demyelinating neuropathy. Between November 2006 and October 2009, four men and one woman aged 52-85 years received intravenous rituximab at 375 mg/m(2) on day 1 and oral fludarabine at 40 mg/m(2)/day from days 1 to 5, in a treatment cycle that was repeated every month for up to 6 months. Two patients had IgM monoclonal gammopathy of undetermined significance and three low tumor mass Waldenstrom's macroglobulinemia. Four patients showed a major hematological response with a decrease in anti-MAG titer in three and clearing in one. One patient did not respond. For the responding patients, symptoms and electrophysiological parameters improved significantly. No patient relapsed at post-RF treatment follow-up (12-45 months), and no toxicity was reported. The combination of RF induced significant responses in IgM anti-MAG demyelinating neuropathies, without toxicity. Clinical improvements were correlated to hematological and immunological results.

Abstract Objective: To assess real-life treatment practices with imatinib for chronic-phase chronic myeloid leukaemia (CP-CML) in France. Research design and methods: In the observational ‘Unmet Needs in CML’ (UNIC) study of CML management in Europe, case report forms were completed retrospectively for eligible patients (≥18 years of age, currently treated for CML) during enrolment (September 2006–March 2007). Results from the subset of patients from France are presented. Main outcome measures: Primary objectives were to estimate from the collected data the proportions of patients ever treated with imatinib and those experiencing imatinib resistance and/or intolerance as determined by physicians’ diagnoses of resistance/intolerance leading to a change in imatinib use. Collected data were analysed descriptively. Secondary descriptive measures included imatinib dose modifications and methods for treatment response monitoring. Results: Of the 654 French CP-CML patients, 95.9% had received imatinib. Of these, 15% were judged by physicians as imatinib-resistant and 31% as imatinib-intolerant (not mutually exclusive) during treatment, 44% required dose modification and 23% discontinued imatinib. In the 12 months preceding the last observation, 65% had a cytogenetic features analysis and 93% had a polymerase chain reaction (PCR) assessment of molecular response. Importantly, and contrasting with European recommendations, 46% of imatinib-resistant patients had never been assessed for BCR-ABL mutations. Limitations: The observational study design limits data collection and interpretation. The findings are specific to the French healthcare system and may not apply to other countries. Conclusion: This observational study of CP-CML management in France confirmed that most patients are treated with imatinib, a treatment widely recognised as efficacious. The study highlights opportunities for optimising CML management, as a proportion of patients may require alternative treatment strategies due to imatinib resistance/intolerance. Response monitoring rates differ from recommendations, representing another opportunity for improving care for CP-CML patients through early identification of patients failing current therapy.

Objectives: This study aimed to provide further clinical evidence for the efficacy and safety of epoetin β once weekly across a wide range of cancer types. Methods: This was a multicenter, open-label, prospective, single-arm study in patients with either a solid tumor or non-myeloid hematological malignancy, receiving or scheduled to receive further chemotherapy. Patients received epoetin β 30,000 IU subcutaneously once weekly for 16 weeks. The primary efficacy endpoint was the change in hemoglobin (Hb) level according to the patient’s baseline Hb level. Results: A total of 691 patients were included in the intent-to-treat population. Epoetin β effectively increased Hb levels (a mean increase from baseline of 1.1 g/dl by week 4 and 2.2 g/dl by week 12). Hb response was achieved in 60.4% of all patients and 61.2% of those with baseline Hb <11 g/dl. Hb response was similar in patients with solid tumors (60.5%) and non-myeloid hematological malignancies (60.2%). Type of chemotherapy and baseline platelet count were independent predictive factors for response. Epoetin β treatment was well tolerated. Conclusions: Epoetin β 30,000 IU once weekly effectively increases Hb levels, is well tolerated and has similar efficacy in anemic patients with solid tumors or non-myeloid hematological malignancies.

V617F JAK2 mutation is a reliable molecular marker of polycythemia vera (PV), potentially useful to monitor the effect of treatments in this disease. In a phase 2 study of pegylated (peg) IFN-alpha-2a in PV, we performed prospective sequential quantitative evaluation of the percentage of mutated JAK2 allele (%V617F) by real-time polymerase chain reaction (PCR). The %V617F decreased in 24 (89%) of 27 treated patients, from a mean of 49% to a mean of 27% (mean decrease of 44%; P < .001), and no evidence for a plateau was observed. In one patient, mutant JAK2 was no longer detectable after 12 months. In 3 patients homozygous for the mutation, reappearance of 50% of wild-type allele was observed during treatment. The results seem to confirm the hypothesis that IFN-alpha preferentially targets the malignant clone in PV and show that %V617F assessment using a quantitative method may provide the first tool to monitor minimal residual disease in PV. This trial was registered at www.clinicaltrials.gov as #NCT00241241.

BACKGROUND AND OBJECTIVES:In non-randomized studies, thalidomide appeared to be effective in myeloid metaplasia with myelofibrosis (MMM). We compared thalidomide to placebo for treatment of anemia in MMM. DESIGN AND METHODS:A prospective phase II B, randomized double-blind multicenter trial comparing thalidomide 400 mg/d with placebo for 180 days was conducted in 52 anemic patients (hemoglobin pounds Sterling 9 g/dL or transfused). The main outcome measure was a 2 g/L increase in hemoglobin or 20% reduction in transfusions. RESULTS:In the thalidomide group only 10 patients completed 6 months of treatment. At 180 days, in an intention-to-treat analysis, no difference was observed between the thalidomide and placebo groups as regards improvement of hemoglobin levels (one patient in each group) or reduction of red blood cell transfusions (three vs five patients, respectively). The spleen size, determined by ultrasonography, increased significantly less in the thalidomide group than in the placebo group (p < 0.05). Thalidomide had no apparent benefit on the Dupriez score, the severity score, survival, death, or any other clinical or biological parameter. Somnolence, gastro-intestinal signs, weight gain, and edema were significantly more frequent in the thalidomide group. Outpatient discontinuation of thalidomide was significantly correlated with a high severity score > 4 (odds ratio, OR = 16; p < 0.01), and g-glutamyl transferase levels > 40 IU/L (OR = 12; p < 0.05). INTERPRETATION AND CONCLUSIONS:Thalidomide (200-400 mg/d) does not demonstrate substantial efficacy in anemic MMM patients. The natural history of disease in the placebo group revealed spontaneous periods of remission of anemia. Tolerance of thalidomide was significantly correlated wih the severity and liver involvement of the disease.