Presence Of Constitutional Symptoms Research Articles

OA21 Clinical outcomes and predictors of difficult-to-treat lupus nephritis: observations from a single center retrospective cohort

Abstract Background/Aims Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE). About 14-33% of LN patients fail to respond to standard treatment. In this study we evaluated the treatment outcomes of LN patients who failed to respond to standard first-line immunosuppressives and attempted to define the clinical characteristics of ‘difficult-to-treat’ (DTT) LN. Methods Records of all SLE patients from the lupus clinic in our center who underwent renal biopsy were reviewed. Those with class III, IV, and V LN were included. Demographic, clinical, laboratory and histopathological features were recorded. Any patient with inadequate response to first-line induction which, according to the ACR, is disease worsening at three months or treatment failure by six months or who did not have partial or complete response as per EULAR/ERA-EDTA definition, were classified as DTT LN. Those who achieved complete response but developed flares within 24 months of therapy warranting second induction were also considered DTT. All of these patients received a second induction therapy. The outcome of interest was a composite outcome of worsening creatinine, end-stage renal disease (ESRD) or death. Secondary outcomes included response rates, time to achieve response, progression to ESRD, mortality, and adverse events. Results We identified 181 SLE patients (91.7% female) with biopsy-proven LN with complete records who had at least 2-year follow-up from 2004 to 2022. Their age (median, IQR) was 29 (24-32) years, median duration of disease 48 (24-84) months, median SLEDAI-2K was 12 (8-16). Among the initial kidney biopsies, 71 (39.2%) were class III, 74 (40.8%) class IV, 23 (12.7%) pure class V and 13 (7.1%) class III/IV + V. Fifty-seven of 181 (31.4%) were identified as DTT. Among these, 28/57 (49.1%) received second induction treatment, 22/57 (38.6%) received three induction, and 7/57 (12.3%) received >3 induction. Being of male sex, presence of constitutional symptoms, serositis, hypertension, leucopenia, active sediments in the initial urinalysis, anti-Ro-60, anti-U1RNP, any antiphospholipid antibodies (aPLs), low C3, wire loop lesions, interstitial inflammation, fibrinoid necrosis, cellular or fibrocellular crescents, and glomerulosclerosis were significantly associated with DTT LN (Table 1). On multivariate logistic regression, only the presence of aPLs and active urinary sediments remained as independent predictors of DTT LN(table 1). A Kaplan-Meier plot showed the cumulative incidence of the composite outcome to be significantly high in the DTT group. After follow up of 250 months, 24/57 (42.1%) DTT patients were in complete remission and 11/57 (19.3%) in partial remission, while 22/57 (38.6%) remained non-responsive to treatment. Conclusion The burden of DTT LN was 30% in our cohort, of whom 65% responded completely to second or third inductions, while a significant proportion failed to achieve remission even with repeat induction. Presence of active sediments at initial diagnosis and co-existence of aPLs were independent predictors of DTT LN. Disclosure J.B. K l: None. A. Jose: None. V. G: None. B. Mashetty: None. G. M s: None. M. Gorijavolu: None. C. Kavadichanda: None. A. Gopal: None. C. Mariaselvam: None. M.M. Thabah: None. V.S. Negi: None.

Essential thrombocythaemia.

Essential thrombocythemia (ET) is a chronic Philadelphia-negative myeloproliferative neoplasm that has its main involvement in the megakaryopoietic lineage, generating sustained thrombocytosis in peripheral blood and an increase in the number of mature megakaryocytes in the bone marrow. In addition to marked thrombocytosis, it is characterized by increased thrombotic or hemorrhagic risk and the presence of constitutional symptoms. Patients with ET have a low but known risk of disease progression to myelofibrosis and/or acute leukemia. The diagnosis is made based on the 2016 WHO criteria. At present, available treatments for patients with ET are mainly aimed at minimizing the risk of thrombosis and/or bleeding.

High Rate of Disease Progression in Patients with Low-Risk Myelofibrosis (MF) Enrolled in the Prospective, Real-World MOST Study

Background: Patients (pts) with low-risk MF are typically excluded from interventional clinical trials, thus data regarding the prognosis of this pt population are largely derived from retrospective analyses. The Myelofibrosis and Essential Thrombocythemia Observational Study (MOST; NCT02953704) is a prospective observational study that enrolled pts with low-risk MF defined by Dynamic International Prognostic Scoring System (DIPSS) criteria. In this analysis, we report disease progression, defined by worsening of clinical or laboratory parameters, in MF pts during the MOST study. Methods: Criteria for enrollment in MOST were confirmed locally and centrally, and included a physician-reported diagnosis of MF (PMF, post-PV, or post-ET) and lack of any DIPSS risk factors except for age >65 y. Of the 232 MF pts enrolled, 205 met this criteria upon central review and were included in this analysis as Cohort A; the remaining 27 pts were enrolled despite having ≥1 DIPSS risk factor (other than age >65 y) and were analyzed separately as Cohort B. Data were collected as previously described (Gerds A. CLML. 2022;22:e532). Disease progression on study was defined as the acquisition of 1 of the following criteria: hemoglobin (Hb) <10 g/dL, platelets <100×10 9/L, presence of constitutional symptoms (weight loss, fever, or sweats), new or worsening splenomegaly, blasts >1%, WBC count >25×10 9/L, death due to disease progression, leukemic transformation (LT), or >1 RBC transfusion. Median (range) follow-up was 52.9 months (42-68). Results: In Cohort A, 120/205 pts (58.5%) had evidence of disease progression during the study. Baseline characteristics comparing pts with vs without disease progression were similar; although compared with pts without progression, those who progressed were older at diagnosis (median [range], 65.9 [21-88] vs 62.9 [35-86] y), older at enrollment (median [range], 70.5 [35-88] vs 66.0 [35-88] y), and had longer median (range) time from diagnosis to enrollment (1.9 [0-38] vs 1.4 [0-24] y). Similar percentages of pts with vs without progression were receiving MF-directed therapy at enrollment (59.2% vs 61.2%); most common treatments were ruxolitinib (33.3% vs 14.1%) and hydroxyurea (22.5% vs 36.5%). Of pts in Cohort A tested for JAK2 mutations, 66/93 (71.0%) with disease progression and 42/65 (64.6%) without were positive. Of pts tested for CALR mutations, 16/21 (76.2%) with disease progression and 17/23 (73.9%) without were positive. Among the 120 pts with progression, 64 (53.3%) met 1 criteria, 27 (22.5%) met 2 criteria, and 29 (24.2%) met ≥3 criteria during the study. The most common progression criteria met were Hb <10 g/dL (47.5%), platelets <100×10 9/L (31.7%), constitutional symptoms (30.8%), and new/worsening splenomegaly (28.3%) (Table 1). Median (95% CI) durations to 1st, 2nd, and 3rd progression criteria were 24.9 (19.2-34.7), 28.2 (14.3-NE), and 11.6 (8.9-26.5) months, respectively (Figure 1). Of pts who progressed, 6 (5.0%) developed LT and 12 (10.0%) died due to disease progression. In Cohort B at time of enrollment, 25/27 pts (92.6%) met 1 progression criteria. The most frequent was Hb <10 g/dL (13/27 [48.1%]), followed by WBC count >25×10 9/L (7/27 [25.9%]); constitutional symptoms (4/27 [14.8%]), and blasts >1% (1/27 [3.7%]); 1 pt (3.7%) met 2 progression criteria (Hb <10 g/dL and constitutional symptoms), and 1 pt (3.7%) met 3 progression criteria (blasts >1%, constitutional symptoms, and WBC count >25×10 9/L). Eight of 27 pts (29.6%) had evidence of further disease progression while on study (Table 1). The most common new progression criteria met were Hb <10 g/dL and platelets <100×10 9/L (each 5/8 [62.5%]) and constitutional symptoms and new/worsening splenomegaly (each 3/8 [37.5%]). Conclusions: This real-world observational analysis from MOST is the first prospective analysis of disease progression in low-risk myelofibrosis. The results show that with over 4 y of follow-up, nearly 60% of pts with low-risk MF had evidence of disease progression; 17/205 pts (8.3%) developed LT or died (both occurred in 1 pt). Median time to acquisition of 1st and 2nd disease progression criteria was approximately 2 y, respectively, decreasing to approximately 1 y for the 3rd criteria; this indicates a slow but increasing rate of progression over the course of the study. These data provide real-world insight into disease progression rate in pts with low-risk myelofibrosis.

Plasmablastic Lymphoma Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database

Background Plasmablastic Lymphoma (PBL) is a rare and aggressive subtype of non-Hodgkin's lymphoma. It tends to be associated with immunosuppressive clinical contexts, such as HIV infection and immunosuppressive therapies for autoimmune disorders and organ transplants. However, due to the rarity of the disease, which is poorly understood, varied treatment approaches have been implemented, and no optimal data or guidelines for managing PBL are available. Furthermore, a few small case series reported conflicting prognosticators. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies influencing survival in this rare disease. Methods To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 300 cases that fit the diagnostic criteria for PBL. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results A total of 300 patients with confirmed PBL were identified. The median age was 49. There was a male preponderance with M:F of 2.7. The median duration of symptoms before diagnosis was 1 month. PBL involved the H&N (39%), Lymph nodes (LN) (33%), GI tract (31%), bone marrow (17%), bones (14%), lungs and pleura (10%), skin (9%), spleen (7%), liver (6%), CNS (6%), and testes (2%). Constitutional symptoms were reported in 35%. Stage III/IV accounted for 51% of the cohort. Sixty-two percent were immunosuppressed, 47% due to HIV. While 58% were Kappa restricted, 40% were Lambda, and 2% null. The median OS and DFS of the whole group were 25 and 15 months, respectively. The involvement of BM (p<0.0001), liver (p=0.003), lungs/pleura (p<0.0001), and upper GI tract (0.001) was associated with worse OS. Moreover, CD4<100 (p=0.006), HHV8+ (p=0.02), EBER-negative (p=0.01), LDH>500 (p=0.04), and stage>2 (p<0.0001) were also associated with worse OS. PBL involving the H&N had better OS (p=0.0001). Though CNS involvement, presence of constitutional symptoms, and MYC+ had numerically worse OS, it did not reach statistical significance. Age, sex, light chain restriction, type of immunosuppression, other organ involvement, and other IHC phenotype did not impact OS. Compared to no treatment, chemotherapy and stem cell transplant had incrementally superior median OS (2 vs. 27 vs. NR months, p<0.0001). Frontline intensive chemotherapy yielded better OS than CHOP-like and myeloma regimens in decreasing order (p<0.0001). Patients who attained CR as their best response also had a superior median OS (p<0.0001). Conclusion This study presents clinicopathologic data from the largest pooled cohort of patients with PBL. It identifies the type of organ involvement, CD4 counts, EBER and HHV8 status, LDH levels, stage, type of therapy, and quality of response to treatment as critical determinants of OS.

ATG/ATLG Improves GvHD-Free and Relapse-Free Survival in Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation

Background Despite recent improvements in the field of JAK inhibitors, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment for patients with myelofibrosis. However, HSCT is associated with a non-negligible treatment-related morbidity and mortality, with graft-versus-host disease (GvHD) being one of the major complications for these patients. In vivo T-cell depletion with antithymocyte/antilymphocyte globulin (ATG/ATLG, short ATG) as part of the conditioning regimen prior to HSCT is widely used as a GvHD prophylaxis, but data on its role in the setting of myelofibrosis is scarce. The aim of this study was to evaluate the impact of ATG on clinical outcomes of patients with myelofibrosis undergoing HSCT in a large international retrospective study. Patients and Methods We leveraged a multicenter collaborative network of 7 European and US academic transplant centers to accrue myelofibrosis patients who underwent first HSCT. The primary endpoint was GvHD-free and relapse-free survival (GRFS), whereas secondary endpoints were acute and chronic GvHD, relapse incidence, non-relapse mortality (NRM), and overall survival (OS). We applied multivariate Cox and Fine & Gray modelling to adjust for potential confounders. In addition, a Dependent Dirichlet Process model for censored data was developed, which can adjust for potential violations of the ubiquitous proportional hazards assumption. Finally, to check results and to obtain another reliable comparison, we applied a propensity score matching of the two groups. Results Overall, we identified 806 patients, of whom 513 received ATG and 293 received non-ATG GvHD prophylaxis. No significant differences were observed between the two groups with regards to median age at HSCT (57 years for both) nor for gender, disease ontogenesis (primary or secondary), frequency of driver mutations, and treatment with ruxolitinib prior to transplant. Patients in the ATG and the non-ATG group differed for other characteristics including splenectomy prior to transplant (8% vs. 20%), donor type (matched related donor (MRD): 21% vs. 39%), Karnofsky Performance Status (<90%: 39% vs. 26%), intensity of conditioning therapy (reduced intensity conditioning (RIC) in 80% vs. 40%) and the presence of constitutional symptoms (58% vs. 44%). Regarding the Dynamic International Prognostic Scoring System (DIPSS), the ATG cohort was more enriched in intermediate-2 and high-risk diseases (64% vs. 58%). Notably, the most common stem cell source in the ATG and the non-ATG cohort was in both cases peripheral blood (98% vs. 95%). The cumulative incidence of acute GvHD grade II-IV was 35% (95% CI, 31-39%) for the ATG group vs. 58% (95% CI, 52-64%) for the non-ATG group (P<0.001). No difference in incidence of chronic GvHD was observed, showing 53% (95% CI, 49-57%) for the ATG group vs. 52% (95% CI, 47-57%) for the non-ATG group (P=0.52). With a median follow-up of 6.5 years for the ATG group and 7 years for the non-ATG group (P=0.10), the 5-year estimates for GRFS were 47% (95% CI, 43-51%) vs. 44% (95% CI, 38-50%; P=0.007; Figure), respectively. The 5-year cumulative incidence of relapse was 14% (95% CI, 10-18%) vs. 13% (95% CI, 8-18%; P=0.62) and the 5-year cumulative incidence of death without relapse for both groups was 28%, respectively (P=0.59). Remarkably, 5-year OS was similar, being 63% (95% CI, 59-67%) for the ATG group vs. 62% (95% CI, 58-68%) for the non-ATG group (P=0.56). Multivariable modelling for GRFS (adjusting for donor type, performance status, conditioning intensity, and DIPSS categories) showed an independent significant reduction in risk for GvHD or relapse in the ATG group (HR=0.85, 95% CI 0.79-0.91; P=0.007). Propensity score matching of 150 pairs confirmed the significant effect of ATG on GRFS (HR 0.90, 95% CI, 0.82-0.98; P=0.03). No differences between the two groups were identified for secondary endpoints of relapse, non-relapse mortality, and overall survival. Conclusion The use of ATG as GvHD prophylaxis in patients with myelofibrosis undergoing HSCT resulted in significantly reduced GRFS. This effect was mainly driven by a significant reduction in acute GvHD.

Blastic Plasmacytoid Dendritic Cell Neoplasm Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with a propensity for cutaneous involvement. This disorder has gone through many reiterations over the years, being classified initially as a blastic NK-cell lymphoma, then a subset of AML, and finally recognized as a unique myeloid neoplasm. However, due to the poor understanding and the rarity of the disease, varied treatment approaches have historically been implemented, and no optimal data or guidelines for managing BPDCN are available. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies that influence survival in this disease. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 273 cases that fit the diagnostic criteria for BPDCN. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 273 patients with confirmed BPDCN were identified. The median age was 61.5. There was a male preponderance with M:F of 2.4. The median duration of symptoms before diagnosis was 5 months. Eighty-one percent of patients presented with skin lesions, 65% of which were disseminated. Involvement of Lymph nodes (LN), bone marrow (BM), spleen, peripheral blood, and CNS occurred in 62%, 73%, 55%, 71%, and 57%. Constitutional symptoms were reported in 13%. The median OS and DFS of the whole group were 16 and 13 months, respectively. Patients younger than 60 had better median OS (30 vs. 10 months, p < 0.0001). The involvement of LN (p = 0.03), BM (p = 0.007), spleen (p = 0.02), and peripheral blood (p = 0.01) was associated with worse OS. Furthermore, disseminated skin involvement had worse OS than focal (p = 0.001). Though CNS involvement, presence of constitutional symptoms, elevated LDH, and TdT negative status had numerically worse OS, it did not reach statistical significance. Sex did not impact OS. Compared to no treatment, non-dose-intense chemotherapy, dose-intense chemotherapy, and stem cell transplant had incrementally superior OS (3 vs. 10 vs. 22 vs. 66 months, p < 0.0001). Patients who attained CR as their best response also had a superior median OS (26 vs. 5 months, p < 0.0001). Conclusions: This study presents updated clinicopathologic data from a large, pooled cohort of patients with BPDCN. It identifies age, organ involvement, type of therapy, and quality of response to treatment as critical determinants of OS.

Mast Cell Leukemia Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database

Background Mast cell leukemia (MstCL) is a rare but aggressive variant of systemic mastocytosis (SM) which is defined by the presence of >20% atypical mast cells in the bone marrow. It is further classified into leukemic and aleukemic variants based on the presence or absence of >10% atypical mast cells in the peripheral blood, respectively. There is a wide variation in treatment regimens used to treat MstCL. Despite this, the prognosis remains poor. The determinants of survival outcomes in this disease are not very well defined. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies that influence survival in this disease. Methods To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 144 cases that fit the diagnostic criteria for MstCL. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results A total of 144 patients with confirmed MstCL were identified. The median age was 58.5. There was a slight female preponderance with F:M of 1.2. The median duration of symptoms before diagnosis was 2 months. Involvement of lymph nodes, spleen, peripheral blood, skin, and CNS occurred in 17%, 44%, 23%, 13%, and 6%, respectively. Constitutional symptoms and hemophagocytosis occurred in 33% and 8% of the cases, respectively. The median OS and DFS of the whole group were 9 and 8 months, respectively. Patients younger than 55 had worse median OS (6 vs. 15 months, p=0.03). Hgb<10g/dl (p=0.0002), Platelets<100K (p=0.01), leukemic phase (p=0.02), and complex cytogenetics (p=0.02) were associated with worse OS. Furthermore, presence of hemophagocytosis had worse OS (p=0.06). Although the presence of constitutional symptoms, Tryptase>200, and KIT mutations other than D816V had numerically worse OS, they did not reach statistical significance. Sex, IHC phenotype, presence of concomitant malignancy, and type of organ involvement did not impact OS. Compared to no treatment, dose-intense chemotherapy, non-dose-intense chemotherapy, novel agents, and stem cell transplant had incrementally superior OS (2 vs. 7 vs. 15 vs. 15 vs. 23 months, p<0.0001). Patients who attained CR as their best response also had a superior median OS compared to responses less than CR and non-responders (NR vs. 29 vs. 8 months, p<0.0001). Conclusion This study presents updated clinicopathologic data from a large, pooled cohort of patients with MstCL. It identifies age, anemia, thrombocytopenia, leukemic presentation, complex cytogenetics, type of therapy, and quality of response to treatment as critical determinants of OS.

Rheumatology experience with FDG PET / CT in inflammation of unknown origin: a single - centre report for determining factors associated with diagnostic precision.

Demographic, clinical and laboratory information of the patients followed up in our clinic and who underwent PET / CT for differential diagnosis were enrolled. Whether they were diagnosed after PET / CT and during the follow - up period, and their diagnoses were examined. A total of 132 patients were included in the study. A previous diagnosis of rheumatic disease was present in 28.8 % of the patients, and a history of malignancy was present in 2.3 % . The patients were divided into three groups: group 1 patients with increased FDG uptake in PET / CT and diagnosis confirmed by PET / CT, group 2 patients with increased FDG uptake in PET / CT but diagnosis was not confirmed, and group 3 patients without increased FDG uptake in PET / CT. Increased FDG uptake in PET / CT was detected in 73 % of the patients. While PET / CT helped the diagnosis in 47 (35.6 %) patients (group 1), it did not help the diagnosis in 85 (64.4 %) (groups 2 and 3). Thirty - one (65.9 %) of the diagnosed patients were diagnosed with a rheumatologic disease. When the 3 groups were compared, male gender, advanced age, CRP levels, presence of constitutional symptoms, SUVmax values and number of different organs with increased FDG uptake were higher in Group 1. Sixty - six percent and 74 % of the patients in groups 2 and 3 were not diagnosed during the follow - up period. No patient in group 3 was diagnosed with malignancy during follow - up. PET / CT has high diagnostic value when combined with clinical and laboratory data in the diagnosis of IUO. Our study revealed that various factors can affect the diagnostic value of PET / CT. Similar to the literature, the statistically significant difference in CRP levels shows that patients with high CRP levels are more likely to be diagnosed with an aetiology in PET / CT. Although detection of involvement in PET / CT is not always diagnostic, there was an important finding that no malignancy was detected in the follow - up in any patient without PET / CT involvement. Key points •PET / CT is an effective method for detecting inflammatory foci. •PET / CT has proven to be effective in the diagnosis of rheumatological diseases, the extent of disease and the evaluation of response to treatment. •Indications for the use of PET / CT in the field of rheumatology and the associated factors and clinical features supporting the diagnosis with PET / CT are still to be fully clarified. •In routine practice, with PET / CT, both delays in diagnosis and examinations performed during diagnosis and the cost can be reduced.

P35 Lupus masquerading as Cholangiocarcinoma: One of the many faces of multifaceted lupus

Introduction/BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune condition which can present with a wide variety of clinical features. This variation can lead to delayed diagnosis or misdiagnosis. Gastroenetrological pathology in SLE is rare but primary autoimmune hepatitis, pancreatitis, lupus enteritis, cholestatic biliary disease and protein losing enteropathy have all been reported. We would like to share the first known presentation of SLE as cholangiocarcinoma.Description/MethodA 62-year-old, previously fit and well, gentleman presented with a 1 month history of painless jaundice, a palpable gallbladder (Courvoisier syndrome), dark urine, pale stool, generalised rash, pruritus, weight loss and anorexia. The presence of these red flag features raised concerns. Initial investigation with Endoscopic retrograde cholangiopancreatography (ERCP) revealed distal common bile duct (CBD) stricture which was further explored with computerised tomography of thorax, abdomen, pelvis and magnetic retrograde cholangiopancreatogram (MRCP) both raising the suspicion of a cholangiocarcinoma in the presence of constitutional symptoms. Several biopsies and brushings taken during multiple ERCP’s failed to identify clear mitotic cells, IgG 4 staining remained negative. Further investigation with Positron emission tomography – computerised tomography (PET-CT) showed significant FDG uptake around the upper part of the stent with final working diagnosis of Cholangiocarcinoma and a Whipple’s procedure was planned.In the interim, the patient developed swollen painful hands, scleritis and a yellow blistering rash. He was referred urgently onto the Rheumatology team after receiving the positive immunology results: ANA (1:1280), Anti double stranded DNA and Rheumatoid Factor (RF) along with hypocomplementemia (C3&C4).Discussion/ResultsSubsequent work up under rheumatology was done considering the possibilities of diagnosis of Systemic lupus erythematosus (SLE), Lupus related autoimmune hepatitis and reactive arthritis as a result of underlying malignancy. Patient’s immunology and other clinical features such as skin rash were strongly supportive of SLE as a primary diagnosis. He was initially treated with low dose prednisolone with dramatic improvement in arthritis and gradual improvement in liver function test. Following MDT discussions with the hepato-biliary team it was felt that lupus was the cause of the biliary stricture which settled well with steroid treatment. A final ERCP was arranged to remove the stent and take final brushings. Methotrexate was started at this point. His SLE remains well controlled on methotrexate and his liver function tests, including bilirubin, remain within the normal range. Patient has now been completely asymptomatic and is discharged from the care of hepatobiliary team with long term follow up for his SLE with rheumatology.Key learning points/ConclusionThis is extremely rare first presentation of SLE presenting with painless jaundice and biliary stricture which improved both biochemically and clinically with treatment of SLE. The key learning points included:Urgent review by rheumatology can facilitate timely diagnosis and preventable admissions/interventions such as major intraabdominal procedure in the form of whipple’s disease planned in our case.Cancer remains a major cause of mortality and morbidity in rheumatological conditions like SLE. Hence initial diagnosis can become extremely difficult if an overlap between these two happens.Treatment options can be limited initially and steroids remain the main stay of treatment till mitotic lesions have been ruled out and disease modifying agents can be used without any contraindications. But disease control for our conditions remains challenging in presence of cancers.

Real-world data of lebanese patients with chronic lymphocytic leukemia.

e19512 Background: Many advances in the treatment of chronic lymphocytic leukemia (CLL) has been made in the 6 past years aiming at attaining durable complete responses and even cure. The choice of upfront therapy is driven by several factors including presence of 17p deletion or TP53 mutation, IGHV mutation status, patient fitness, comorbidities, drug availability and affordability etc.. The aim of the current study was to describe aspects of CLL in real world data setting in Lebanon regarding patients’ characteristics, diagnostic studies, indications for therapy and implication of new treatments including small molecule inhibitors including Bruton Tyrosine Kinase BTK and BCL2 inhibitors. Methods: This was an observational prospective study (2004-2021) of consecutively diagnosed patients with CLL at a single center in Lebanon. The characteristics, indication for treatment, types of treatment used were recorded progression free survival (PFS) was defined as the time from treatment initiation at first line until progression from any cause. Results: The registry covered 128 patients, 82 males and 46 females (ratio 1.78:1). Median age at diagnosis was 66 years. 23.6% were younger than 55 years. 73% of patients were asymptomatic at diagnosis, and 25% had lymphadenopathies. RAI stage 0 (BINET stage A) was observed in 73%. Median absolute lymphocytic count was 15,340 (unit), median hemoglobin was13.2. and median platelet count was 188,000. FISH panel was done in 56 patients (43%) and IGHV in 13%. 17p deletion was detected in 14.3%, and 13q deletion as a sole abnormality in 46.6%. 15.7% of patients required treatment at diagnosis; 52.6 % of them due to anemia/thrombocytopenia, and 15.8% due to presence of constitutional symptoms; other treatment indications included massive splenomegaly, and massive or symptomatic lymphadenopathy. 71 patients (55.4%) fell into the watch and wait category; 37 of which required treatment at some point during follow up with a median duration from diagnosis till starting treatment of 34 months.FCR Fludarabine + cyclophosphamide + rituximab (38.5%), BR bendamustine + Rituximab (23%), and Ibrutinib (19.2%) were the most common regimens used upfront. PFS was not reached. and correlation between genetic features and survival couldn’t be done, due to the relatively small number of patients whom showed progression. Conclusions: Epidemiologic characteristics of Lebanese patients with CLL is comparable to the international data.Molecular studies are being more implicated in the diagnostic workup. FCR and BR were mostly used upfront during the previous decade. We noticed a trend toward using Ibrutinib after 2016 in frontline and relapsed setting (after its approval and availability).

Unexplained fever, weight loss, and worsened dyspnea with pulmonary hypertension as the presenting symptoms of mixed connective tissue disease with interstitial lung disease: A case report with review of literature

Pulmonary manifestations of mixed connective tissue disease (MCTD) include as bronchiolitis, bronchiectasis, and interstitial lung disease with or without pulmonary hypertension. Tuberculosis (TB) is the most common diagnosis in India in the presence of constitutional symptoms such as cough, fever, and weight loss with lung parenchymal abnormality, irrespective of microscopic or nucleic acid amplification test abnormalities due to high tuberculosis prevalent tropical setting. In this case report, a 35 year old female presented with constitutional symptoms and lung parenchymal nodules, interstitial involvement with lung fibrosis and pulmonary hypertension. Mediastinal window documented necrotic mediastinal lymph nodes, without negative mycobacterial microscopic (smear examination) or genome documentation (Gene Xpert MTB/RIF). She had received empirical anti tuberculosis treatment for three months without clinical or radiological response, resulted in progression of disease with clinical and radiological worsening and referred to our unit for further workup. Bronchoscopy guided evaluation for tropical screen including bacterial, fungal and tuberculosis with malignancy was inconclusive. Vasculitis and CTD workup documented antinuclear antibody (ANA) test strongly positive with very highly raised titres, with positive antigen as U1 small nuclear ribonucleoprotein particle, SSA/RO, single strand DNA, and Scl 70. Treatment initiated with systemic steroids, tadalafil, mycophenolate and diuretics, and satisfactory clinical response documented as near complete resolution of pulmonary parenchymal abnormalities in 24 weeks and pulmonary hypertension in 12 weeks. Pulmonary manifestations of MCTD are common, underestimated in the presence of constitutional symptoms, and early pickup of entity in course of illness will have good outcome with excellent prognosis.

Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes

Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes

The Relationship between Cause of Death in Myelofibrosis and the Dynamic International Prognostic Scoring System

Background:The Dynamic International Prognostic Scoring System (DIPSS) and DIPSS Plus are well established systems for providing prognoses to patients with primary myelofibrosis. Five risk factors are included in the DIPSS: age > 65, hemoglobin < 10 g/dL, leukocyte count > 25 x 109/L, circulating blasts ≥ 1%, and presence of constitutional symptoms. The DIPSS plus score also factors in three additional variables: presence of an unfavorable karyotype, transfusion dependency, and platelet count < 100 x 109/L. The bulk of current research focuses on overall survival. The goal of this study was to examine if the presence of these risk factors were associated with cause of death (COD) in patients with myelofibrosis (MF).Methods:Follow-up information on 139 patients referred to Michigan Medicine with an initial diagnosis of myelofibrosis, who subsequently died between April 2007 and February 2017, was collected through retrospective chart review. Nine patients who had an unknown cause of death (COD), and 17 who died from complications due to BMT were excluded, leaving 113 evaluable patients (61 male, 52 female). DIPSS plus risk factors were collected at time of referral, though there was insufficient data available to include an analysis of transfusion-dependency or karyotype. P-values were obtained from a chi-squared test for independence between each variable and COD.PatientsThe median age at diagnosis was 70.7 years (IQR 63.0, 74.9), the median age at death was 73.1 years (IQR 65.8, 77.9), and the median time from diagnosis to death was 2.3 years (IQR 0.9, 4.0). 61.9% of patients had primary MF (n = 86), 23.0% had post-essential thrombocythemia MF (n = 32), and 14.4% had post-polycythemia vera MF (n = 20); one patient's history was unknown. 48.2% had a positive JAK2 mutation (n = 67), 24.5% were tested and negative (n = 34); 12 patient's JAK2 mutation status were unknown.Results:Seven causes of death were predefined, namely death from acute myeloid leukemia (n = 26), bone marrow failure (n = 21), congestive heart failure or pulmonary hypertension (n = 20), spleen or liver complications (n = 17), infection not related to cytopenias (n = 7), failure to thrive (n = 7), or any other COD (n = 15). Among the seven characteristics, a significant association was observed among patients with a platelet count < 100 x 109/L; disproportionately more died due to bone marrow failure and less died due to cardiac or pulmonary causes (p = 0.012). This should be interpreted in the context of no statistically significant associations between COD and the other five clinical risk factors. Overall DIPSS score ≥ intermediate-2 also did not lead to significant associations. Of the 113 patients, sixteen had missing DIPSS scores and/or unknown JAK2 status. Among the remaining 97, a larger-than-expected number of patients with a JAK2 mutation had an Intermediate-1 DIPSS risk; conversely, more patients without a JAK2 mutation had an Intermediate-2 risk. A statistical test for independence yielded a p = 0.009, suggesting that patients with JAK2 mutations have lower DIPSS-calculated risk.Conclusions:DIPSS Plus variables are often collected at referral to provide prognostic information to patients. It appears that the presence of thrombocytopenia is more likely to predict bone marrow failure as a patient's ultimate COD compared to the presence of anemia. Additionally, patients with JAK2 mutations seem to have lower DIPSS-calculated risk. Knowledge of this clinical information can aid management of myelofibrosis. DisclosuresTalpaz:ARIAD: Other: Travel, Research Funding; Pfizer Inc: Consultancy, Other: Travel, Research Funding.

Validation of the Myelofibrosis Secondary to PV and ET-Prognostic Model in Patients with Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis: MD Anderson Cancer Center

Validation of the Myelofibrosis Secondary to PV and ET-Prognostic Model in Patients with Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis: MD Anderson Cancer Center

Psoas muscle index at the time of diagnosis might reflect the prognosis of classical Hodgkin's lymphoma patients.

We retrospectively investigated clinical and prognostic significance of psoas muscle index (PMI) calculated as total psoas muscle area at L3 vertebra level obtained from baseline computed tomography (CT) scans in 49 newly diagnosed classical Hodgkin's lymphoma (cHL) patients prior to specific treatment. Median PMI was 572.5 mm2/m2 and was significantly higher in males (P < 0.001), patients with higher body mass index (BMI, P < 0.001), absence of extranodal disease (P = 0.037), higher absolute lymphocyte count (P = 0.037), higher hemoglobin (P = 0.010) and lower lactate dehydrogenase (LDH, P = 0.050). There were no significant associations with age, disease subtype, presence of constitutional symptoms, Ann Arbor disease stage, presence of advanced disease or international prognostic score. Patients with lower PMI had significantly worse PFS (hazard ratio [HR] 4.91; P = 0.009). This phenomenon persisted in the multivariate model (HR = 5.09; P = 0.042) adjusted for International Prognostic Score (IPS) and chemotherapy type.

Cluster of Differentiation 20 Expression and Rituximab Use Do Not Improve Outcome of Classical Hodgkin Lymphoma Patients

Introduction: Cluster of differentiation 20 (CD20) is expressed in Reed Sternberg (RS) cells of 11-35% of classical Hodgkin lymphoma (cHL) cases with very controversial prognostic significance. Rituximab is not considered part of standard therapy in cHL but has shown promising responses in the relapsed setting. Early metabolic response has emerged as a robust prognostic tool for early and advanced stage cHL. This analysis reports the prognostic significance of CD20 expression and the therapeutic effect of rituximab in 310 previously untreated cHL patients. Methods: After due approval, all newly diagnosed cHL cases were retrospectively identified. CD20 immunehistochemical (IHC) stain was applied to all cases and considered positive when 10% of the RS cells showed expression. Overall survival (OS) and progression free survival (PFS) were computed using Kaplan-Meir method with log ranks test. Multivariate analyses for PFS were computed using Cox regression modeling incorporating variables with a p value ≤ 0.15 from the univariable model in addition to CD20 expression and rituximab use. Results: A: General characteristics Among 310 patients, 171 (55%) were males, the median age was 27 (14-89) years. Stage of disease was advanced (including early unfavorable) in 278 (90%), 214 (70%) had constitutional symptoms and 58 (19%) had bulky disease. The most common subtype was cHL-nodular sclerosis (NS) at 185 (60%). CD20 was positive in 66 (22%) of the cases. Majority of patients received ABVD 234 (76%) and out of the 66 patients with CD20 expression, 27 (41 %) received rituximab with front line chemotherapy. B: Characteristics and outcome based on CD20 expression Stratified by CD20 expression, there was no significant difference in terms of age, gender, stage at presentation, presence of constitutional symptoms or bulky disease between CD20+ and CD20- cases. NS subtype was more common among CD20- cases (p = 0.0001). More patients were able to achieve interim complete metabolic response (CMR) among CD20+ compared to CD20- at 85% vs. 69%, respectively (p = 0.032); this is further detailed in table I. After a median follow up of 51.3 (1.3-213) months, the 3-year PFS was 75.1% for CD20+ and 70% for CD20- (p = 0.36); this is further illustrated in figure I. C: Impact of rituximab therapy on CD20 positive cHL Stratifying CD20+ cases by rituximab therapy, there was no significant difference in terms of age, gender, stage at presentation, presence of constitutional symptoms or bulky disease. First line chemotherapy used was comparable; however more patients received involved field radiotherapy (IFRT) in the no rituximab group (p = 0.05). The addition of rituximab to chemotherapy did not affect the result of interim PET/CT (p = 0.84). Among the CD20+ cases, 27 (41 %) received rituximab with their first line chemotherapy. After a median follow up of 42.6 (1.3-188) months for CD20+ and 55.2 (2.2-213) months for the CD20- group, the 3-year PFS was 75.1% for CD20+ and 70% for CD20-; the 3-year OS was 89.2% for CD20+and 92.8% for CD20- (p = 0.36). After a median follow up of 36 (6.8-116) months for rituximab group and 55.8 (1.3-188) months for the no rituximab group, the 3-year PFS was 72.6% and 67.8% (p = 0.23) while the 3-year OS was 92.6% and 86.6% (p = 0.47)), respectively. This is further illustrated in figure I. On multivariate analysis the presence of constitutional symptoms and interim PET/CT positivity was significantly associated with worse outcome at HR 3.2 (1.14-9.01; p = 0.028) and 4.3 (2.27-8.1; p &amp;lt; 0.0001) respectively. Conclusions: We observed that neither CD20 expression nor nor rituximab use has improved the outcome of cHL patients. The presence of constitutional symptoms and interim PET/CT positivity were associated with worse outcome. A large prospective study is needed to confirm these findings. ptoms and interim PET/CT positivity are associated with worse outcome. A large prospective study is needed to confirm these findings. Figure Disclosures No relevant conflicts of interest to declare.

C reactive protein to albumin ratio as prognostic marker in primary and secondary myelofibrosis

We retrospectively investigated C reactive protein to albumin ratio (CAR) in a cohort of 142 patients with myelofibrosis [101 primary (PMF); 41 secondary (SMF)] and compared it to hematological and clinical parameters. Among other associations, higher CAR was significantly associated with higher grade of bone marrow fibrosis, lower frequency of Calreticulin (CALR) mutations, presence of constitutional symptoms, massive splenomegaly, transfusion dependency, blast phase disease, lower hemoglobin, lower platelets, higher ferritin and higher lactate dehydrogenase (LDH) (p < .05 for all analyses). Higher CAR was able to predict inferior survival in PMF independently of DIPSS [hazard ratio (HR)=2.17; p = .015 for high CAR and HR = 2.05; p < .001 for DIPSS] and in SMF independently of Mysec-PM (HR = 6.48; p = .022 for high CAR and HR = 2.63; p = .013 for Mysec-PM) demonstrating its good prognostic potential. CAR seems to be an independent and prognostically relevant parameter, both in PMF and SMF, and might aid in timely recognition of most vulnerable patients.

Updated Results from the German Mpnsg-0212 Combination Trial: Ruxolitinib Plus Pomalidomide in Myelofibrosis with Anemia

Updated Results from the German Mpnsg-0212 Combination Trial: Ruxolitinib Plus Pomalidomide in Myelofibrosis with Anemia

Impact of Bone Marrow Fibrosis Grade in Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis. a Study of the Mysec Group

Impact of Bone Marrow Fibrosis Grade in Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis. a Study of the Mysec Group

Current Treatments Do Not Improve the Prognosis of Patients with Atypical CML and Unclassified MDS/MPN. a Joint Report from Fi-LMC, FIM, Gfch and GFM

Background Atypical CML (aCML) is a rare myeloid neoplasm with molecular heterogeneity and overlapping features of MDS and MPN. Distinction from unclassified MDS/MPNu based on WHO criteria remains difficult, and the management of these closely related entities remains ill-codified. Most patients (pts) are managed with cytoreductive agents, but small series have reported responses to hypomethylating agents or tyrosine kinase inhibitors (TKI), notably ruxolitinib. Allogeneic stem cell transplantation (SCT) is considered the only curative option. To instruct clinical trials with novel agents in this rare and heterogeneous population, real-life cohorts must i) provide prognostic factors and molecular characterization able to stratify patients, and ii) benchmark outcomes with current treatment options. Methods The French National observational study of rare MDS/MPNs performed a retrospective analysis of adult patients with MDS/MPN from 35 centers. Cases were centrally reclassified according to the 2016 WHO criteria to exclude CMML, classical MPNs and CNL. All statistical analyses were done without dichotomizing continuous clinical or biological variables. The prognostic influence of treatments was analyzed considering onset of treatment as a time-dependent covariate (Mantel-Byar method). Results The study population included 136 pts (M/F 83/53), with a median age of 72 years. Only 43 (31.6%) met WHO 2016 criteria for aCML while the remaining 93 were classified as MDS/MPNu. At diagnosis, spleen enlargement or other tumor symptoms were present in 36% of pts, while 32% had constitutional symptoms. Mutations in ASXL1, splice genes (U2AF1, SF3B1, SRSF2 or ZRSR2), SETBP1, EZH2, CSF3R, JAK2 and ETNK1 were present in 68.8%, 50.0%, 30.3%, 15.9%, 12.7%, 12.6% and 7.4% of 63 tested cases, respectively. 25 pts had an AML transformation. With a median follow-up of 29.8 months (0.5-276.4) median overall survival (OS) and AML-free survival (AMLFS) were 25.6 and 20.6 months, resp. Median OS was 20.2 versus (vs) 29.7 months in aCML vs MDS/MPNu, resp (log rank test p=0.2) and median AMLFS was 16.6 vs 27.4 months, resp (p=0.09). In univariate analysis, higher WBC (p=0.003) and lower Hb level (p&lt;10-5) predicted significantly shorter OS, while presence of splenomegaly or other tumor symptoms (p=0.08), higher proportion of IMC (p=0.06), lower platelet count (p=0.08) and dyserythropoieisis (p=0.05) tended to shorten OS. Age, gender, presence of constitutional symptoms, bone marrow or peripheral blast percentage or dysmegakaryopoiesis had no significant impact (all p&gt;0.1). Patients with EZH2 mutations had shorter OS (median 9.9 vs 20.6 months in EZH2 wt pts, p=0.03), while other gene mutations had no significant prognostic impact (all p&gt;0.1). All variables with p &lt;0.1 in univariate analyses were included in a multivariate Cox model. After backward selection, only Hb levels (HR= 0.81, p&lt;10-5) and dyserythropoiesis (HR=2.4, p=0.04) retained independent prognostic value. At any time during follow-up, 89 (65.4%) pts received cytoreductive agents (mostly hydroxyurea), while 23 (16.9%) received TKI (ruxolitinib in 12, imatinib in 8, dasatinib in 3 pts) and 18 (13.2%) HMA, resp. Of note, 8/18 pts received HMA at transformation to AML, while all pts received TKIs prior to AML. Finally, 19 pts (14.0%) received an SCT and 35.3% received ≥2 of the above-mentioned types of treatment. Median time to SCT, HMA and TKI were 10.2, 11.9 and 4.7 months, resp. In multivariate Cox models adjusting for baseline Hb level and dyserythropoieisis, neither cytoreduction (p=0.6) nor SCT (p=0.5) were associated with a significant OS improvement. Treatment with HMA was associated with a significantly worse OS (HR=3.0, p=0.001), but this effect was confounded when transformation to AML, as a time-dependent event, was included in the model (HMA: HR= 1.1, p=0.7, AML: HR=5.1, p&lt;10-6). Finally, treatment with TKIs was also associated with significantly worse OS (HR=2.3, p=0.02). This TKI's detrimental effect was confirmed in a model also accounting for baseline WHO, (log-transformed) WBC count, platelet levels and bone marrow blast percentage. Conclusions Anemia and dyserythropoiesis are important prognostic factors in aCML and MDS/MPNu that should be used to stratify pts included in clinical trials. There is currently no standard of care for these overlap syndromes. Treatment with HMAs and TKIs should be restricted to clinical trials. Disclosures Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Roy:Incyte Biosciences: Consultancy. Caers:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Legros:Novartis: Honoraria; BMS: Honoraria; Incyte Biosciences: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.