The cornerstone of life-saving therapy in immune mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody, trialled in two multicentre, randomised-placebo-controlled trials leading to EU and FDA approval, has been available in the UK through a patient-access scheme. Data was collected retrospectively from 2018-2020 for 85 patients receiving caplacizumab, including 4 children, from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial endpoints and historical outcomes in the pre-caplacizumab era. 84/85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalisation (3 days), duration of PEX (7 days) and hospital stay (12 days) was comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalisation was favourable compared with historical outcomes (p<0.05). TTP recurrence occurred in 5/85 patients; all with persistent ADAMTS13 activity <5iu/dL. Of 31 adverse events in 26 patients, 17/31 (55%) were bleeding episodes and 5/31 (16%) were thrombotic events (two unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4/5 deaths caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients receiving caplacizumab outside clinical trials, including paediatric patients. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.
Background. Optimal upfront therapy for posttransplant lymphoproliferative disease (PTLD) arising after solid organ transplant remains contentious. Rituximab monotherapy (R-Mono) in unselected patients has shown a lack of durable remissions. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-based chemotherapy confers improved response rates, although concerns exist about toxicity. Methods. This multicenter retrospective study reports outcomes for adults with biopsy-proven B-cell PTLD treated initially with R-Mono or Rituximab plus CHOP (R-CHOP). Selection of therapy was made according to physician preference. Results. Among 101 patients, 41 received R-Mono and 60 had R-CHOP. Most (93%) had undergone renal or liver transplantation. R-CHOP showed a trend toward improved complete (53% versus 71%; P = 0.066) and overall (75% versus 90%; P = 0.054) response rates. In the R-Mono group, 13 of 41 (32%) subsequently received chemotherapy, while 25 of 41 (61%) remained progression-free without further therapy. With median follow-up of 47 months, overall survival (OS) was similar for R-Mono and R-CHOP, with 3-year OS of 71% and 63%, respectively (P = 0.722). Non-PTLD mortality was 3 of 41 (7%) and 4 of 60 (7%) within 12 months of R-Mono or R-CHOP, respectively. The International Prognostic Index was statistically significant, with low- (0–2 points) and high-risk (≥3 points) groups exhibiting 3-year OS of 78% and 54%, respectively (P = 0.0003). In low-risk PTLD, outcomes were similar between therapies. However, in high-risk disease R-Mono conferred an inferior complete response rate (21% versus 68%; P = 0.006), albeit with no impact on survival. Conclusions. Our data support R-Mono as initial therapy for PTLD arising after renal or liver transplantation. However, upfront R-CHOP may benefit selected high-risk cases in whom rapid attainment of response is desirable.
3478 Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of hematopoietic stem cells characterised by deficiency of cell membrane glycosylphosphatidylinositol-anchored proteins, rendering the cells susceptible to complement attack. Budd-Chiari syndrome (BCS) describes obstruction of the hepatic venous outflow tract. Complications such as ascites and varices often occur at the time of acute thrombosis. Conventional management includes anticoagulation, transjugular intrahepatic portosystemic shunt (TIPSS) placement, peripheral/local thrombolysis and orthotopic liver transplantation (OLT). The morbidity and mortality of PNH patients with BCS is particularly high: a new thrombotic event or thrombosis extension in anticoagulated patients is reported in 27%; a significant proportion of TIPSS fail due to recurrent thromboses; historically, mortality rates of 67% have been reported; hematopoietic stem cell transplantation and OLT have unacceptably high transplant-related mortalities. Eculizumab prevents cleavage of C5 and reduces risk of thrombosis in PNH. The role of this monoclonal antibody in the management of BCS with PNH has yet to be evaluated. Nineteen PNH patients (12 female, 7 male) with a BCS diagnosis who were subsequently given eculizumab, were identified from the Leeds PNH Service. Patients were diagnosed with PNH between 1991–2012 (median follow up from PNH diagnosis 7.5 yrs, range 2 mths – 21 yrs; from BCS diagnosis 3.5 yrs). Median age at PNH diagnosis was 30 yrs (range 19–87) and at BCS 32 yrs (range 19–87). The mean granulocyte clone size at PNH diagnosis (n=14) was 86.3% (range 59.7–99%) and at BCS (n=12) was 93.1% (range 80.9–99.6%). BCS was the presenting feature of PNH in 9 (47.4%). Six were diagnosed as part of diagnostic work-up during the acute BCS. In 3, a diagnosis of PNH was made 1, 6 and 26 months post BCS. Ten (52.6%) were already known PNH at the time of their BCS. None were receiving eculizumab. Median time from PNH to BCS was 30 mths, range 3–132. Seven were anticoagulated (5 primary prophylaxis) prior to BCS. Eight PNH patients (Group 1) developed BCS before the availability of eculizumab and remained alive long enough to receive therapy. Six in Group 1 (75%) developed BCS complications prior to commencing eculizumab including development of varices (n=1), progression of thrombus despite full anticoagulation (n=1), ascites necessitating TIPSS (n=2), hepatomegaly (n=3) and splenomegaly (n=3). Two did not endure BCS complications but suffered cerebral vein thrombotic events on anticoagulation. The median time to first dose of eculizumab therapy in Group 1 was 3 yrs (range 2 mths – 11 yrs). All patients remain on eculizumab (median follow-up 6.9 yrs, range 2.8 – 7.1); there have been no further thrombotic events in this cohort. Group 2 consists of 11 PNH patients in whom BCS was diagnosed during the availability of eculizumab. Four received this less than 14 days from onset of BCS without any subsequent complications. The remaining 7 started eculizumab 2 or more weeks from probable onset of BCS. Complications included ascites necessitating TIPSS and/or gastric/esophageal varices. TIPSS procedures were effective in all patients once on eculizumab with no occlusions. Importantly, 3 of the 19 patients have stopped secondary anticoagulation after starting eculizumab (due to thrombocytopenia, hemorrhage or perceived bleeding risk due to varices). There have been no further thrombotic episodes in these patients. This case series is the first to document 19 patients, managed with eculizumab with both PNH and BCS. Rapid intervention with eculizumab in addition to anticoagulation when safe to administer, appears to prevent the development of BCS associated complications. If complications are established at diagnosis, eculizumab can prevent progression and reoccurrence; it also facilitates successful use of TIPSS. We can conclude: a) primary prophylaxis is not sufficient to prevent BCS in patients with PNH b) prompt treatment with eculizumab may negate long-term complications of BCS and allows effective and safe use of TIPSS c) in selected cases, eculizumab therapy may facilitate the withdrawal of anticoagulation without increasing subsequent risk of thrombosis and d) survival for this cohort is currently 100%. The management of BCS in PNH with immediate commencement of eculizumab and, where appropriate, use of TIPSS, is associated with improved outcomes. Disclosures: Kelly: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Richards:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Arnold:Alexion Pharmaceuticals, Inc: Honoraria. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hill:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria.
Post-transplant lymphoproliferative disease (PTLD) remains an important complication of solid organ transplantation. For B-cell PTLD, current first line therapies are Rituximab monotherapy (R-Mono) or R-CHOP. However, optimal selection of initial treatment is challenging due to concerns about the relative efficacy and toxicity of these modalities, and because of uncertainty about the prognostic value of baseline factors. This retrospective study identified 72 biopsy-proven cases of PTLD, diagnosed between 2000 and 2012, from 4 UK centres. These included 34 liver, 32 renal and 6 cardiothoracic transplant recipients. The median age at histological diagnosis was 47 years (range 16 - 72 years) and 68% were male. The median time from transplant to diagnosis of PTLD was 93 months (range 2 – 302 months), with 83% of cases occurring after 1 year. Tumour histology included 14 polymorphic and 49 monomorphic lesions (including 34 diffuse large B-cell, 5 plasmablastic, 4 Hodgkin and 1 T-cell lymphomas) whilst in 9 cases the PTLD subtype was unspecified. EBV-association was noted in 39/72 (54%) and this was significantly related to disease presenting within a year of transplant (X2 p=0.004). Initial therapy was R-Mono in 16/72 (22%) and R-CHOP in 34/72 (47%). Selection of R-CHOP versus R-Mono was significantly associated with stage ≥3 disease (odds ratio [OR] 6.7, p=0.01), onset more than 1 year after transplant (OR 7.3, p=0.03), lack of EBV association (OR 0.1, p=0.002) and monomorphic versus polymorphic histology (OR 14.0, p=0.004). In a multivariate logistic model, advanced stage (OR 11.0, p=0.06) and monomorphic histology (OR 8.5, p=0.03) retained significance. Of patients who received R-Mono, 15/16 (94%) completed at least 4 infusions, with no treatment-related deaths. Of these, 4 patients subsequently received R-CHOP for consolidation of response (2 patients) or for relapsed / refractory disease (2 patients). Of those who received R-CHOP as initial therapy, 23/34 (68%) completed at least 6 cycles, with 4 treatment-related deaths. The overall response rate to R-Mono was 81% (10 CR [complete remission], 3 PR [partial remission] and 3 NR [no remission]), similar to that of R-CHOP at 74% (19 CR, 6 PR, 5 NR and 4 undetermined; X2 p=0.67). With a median follow-up of 38 months, survival outcomes for R-Mono and R-CHOP were 2 year Event-Free Survival of 62% and 54% (p=0.77), 2 year Progression-Free Survival of 67% and 58% (p=0.48) and 2 year Overall Survival (OS) of 74% and 59% (p=0.52; Figure 1A) respectively. Amongst all study patients, significant baseline predictors of (inferior) OS were age ≥50 years (HR 2.9, p=0.006), stage ≥2 disease (HR 4.9, p=0.003), ECOG performance status ≥2 (HR 2.1, p=0.05), and elevated LDH (HR 2.2, p=0.08 borderline significance). Extra-nodal disease, histology, EBV-association and time from transplant were not predictive. In multivariate analysis, age>50 (HR 3.2, p=0.01) and advanced stage (HR 4.0, p=0.02) retained significance. Importantly, amongst those treated with R-Mono or R-CHOP, response to initial therapy was highly predictive of OS (overall response, HR 0.2, p<0.0001; complete response, HR 0.1, p<0.0001). Applying a 4 point modified prognostic index comprised of age>50, stage ≥2 disease, ECOG performance status ≥2 and elevated LDH, patients treated with R-Mono or R-CHOP with low risk disease (<2 points) had significantly improved survival compared to those with high risk disease (≥2 points), with 2 year OS of 90% versus 43% (p=0.001, Figure 1B). Notably, comparison of outcomes for R-Mono versus R-CHOP within high risk or low risk groups revealed no significant differences in survival. However, there was a trend towards inferior response amongst patients with high risk disease treated with R-Mono compared to R-CHOP (CR rate 1/6 [17%] versus 9/16 [56%]; X2 p=0.16), which was not observed for low risk disease. We report outcomes for R-Mono versus R-CHOP as initial therapy for PTLD arising after adult solid organ transplantation. Whilst R-CHOP is associated with greater toxicity, R-Mono may deliver inferior response rates in patients with high risk disease. Survival outcomes were not significantly different between therapies. Importantly, using a modified prognostic index we identify a subset of patients with high risk disease who exhibit very poor outcome, irrespective of initial treatment, for whom novel therapeutic strategies are urgently required. Disclosures: Chaganti: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees.
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