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Journal of the American College of Cardiology ; 79(9):1784-1784, 2022.
Article in English | Web of Science | ID: covidwho-1849088
Blood ; 138:642, 2021.
Article in English | EMBASE | ID: covidwho-1582224


Introduction: The most effective chemoimmunotherapy (CIT) in previously untreated CLL is the combination of fludarabine, cyclophosphamide and rituximab (FCR). Ibrutinib (I), the first irreversible inhibitor of Bruton's tyrosine kinase approved for CLL, has improved outcomes in numerous clinical trials compared to different CIT. Methods: FLAIR (ISRCTN01844152) is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to the IWCLL 2008 guidelines. Patients over 75 years or with >20% 17p-deleted cells were excluded. Participants were randomised on a 1:1 basis to receive 6 cycles of FCR (oral fludarabine 24mg/m 2/day for 5 days, oral cyclophosphamide 150mg/m 2/day for 5 days with IV rituximab [375 mg/m 2 on day 1/2 of cycle 1;500 mg/m 2 on day 1 of cycles 2-6]) every 28-days or IR (Ibrutinib [420mg/day] plus rituximab [6 doses as for FCR]) given for up to 6 years with stratification by disease stage, age, gender and centre. The primary endpoint was to assess whether IR was superior to FCR in terms of investigator-assessed PFS. Secondary endpoints included overall survival,;attainment of undetectable MRD;response to therapy;safety and toxicity;health-related quality of life and cost-effectiveness. A formal interim analysis was planned when 191 events were observed in both arms or 109 events in the FCR arm alone with a p-value of 0.005 leading to reporting of the trial. Here we report the results of this planned interim analysis. Results: A total of 771 patients were randomised (385 to FCR and 386 to IR) from 113 UK Centres between 9/19/2014 and 7/19/2018. The data was locked on 5/24/2021. 73.3% were male, median age was 62 years (33.6% >65yo) and 45.1% were Binet Stage C. IGHV data was available for 728 (94.4%) patients with 53.2% IGHV unmutated (≥98% homology to germline), 40.5% IGHV mutated and 6.3% Subset 2. Hierarchical FISH testing revealed 0.4% 17p del, 15.4% 11q del, 12.3% trisomy 12, 29.7% normal and 35% 13q del;with 7.1% failed. The arms were well-balanced for disease variables with no significance differences. Median follow-up was 52.7 months. IR had a superior PFS compared to FCR (Median PFS not reached for IR versus 67 months for FCR;HR: 0.44;p<0.001;see Figure). The PFS was significantly better for IR in patients with IGHV unmutated CLL (HR: 0.41;p<0.001), but not for patients with IGHV mutated CLL at this follow-up (HR: 0.66;p=0.179). There was no difference in overall survival between the two arms (HR: 1.01;p=0.956) with a total of 29 deaths in FCR arm (including 4 from CLL, 3 Richter's [RT], 3 AML/MDS, 3 COVID-19 and 2 cardiac/sudden) and 30 in the IR arm (including 3 CLL, 1 RT, 0 AML/MDS, 3 COVID-19 and 8 cardiac/sudden). Second line treatment was initiated for 59 patients after FCR (including 38 BTKi, 7 venetoclax+R [venR], 4 BendamustineR [BR] and 3 CHOP-R [RT]) and 21 after IR (including 7 FCR, 5 venR, 1 BR, 1 CHOP-R [RT], 1 ABVD [Hodgkin's]). Overall, 88.1% of patients have received targeted therapies for CLL progression after FCR. The overall survival with FCR in FLAIR is significantly improved compared to FCR in previous NCRI trials (ADMIRE and ARCTIC) which had the same inclusion criteria, the same Centres and an identical FCR schedule, but were conducted prior to widespread availability of targeted therapies in the relapse (recruited between 2009 and 2012). The 4 year overall survival for FCR in FLAIR was 94.5% compared to 84.2% for FCR between 2009 and 2012. SAEs were reported in 53.7% of patients on FCR and 53.4% on IR. Notable differences for SAEs by organ class for FCR vs IR: infections in 33.6% of patients vs 27.1%;blood and lymphatic in 19.8% vs 10.7%;and cardiac in 1.1% vs 8.3%. With current follow-up, there were 10 sudden or cardiac deaths: 8 IR and 2 FCR. Further analysis indicated that 7 of the 8 cardiac or sudden deaths in the IR arm had a history of hypertension or cardiac disease (further detailed in additional ;Munir et al.). Neither of the sudden deaths in the FCR arm ad a prior cardiac or hypertensive history or were on cardiac or anti-hypertensive treatment. There were 6 cases of secondary MDS/AML in the FCR arm and 1 in the IR arm. Conclusion: Ibrutinib plus rituximab resulted in a superior PFS compared to FCR. There was no difference in overall survival, most likely due to effective second-line targeted therapy in patients progressing after FCR. [Formula presented] Disclosures: Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding;AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding;Pharmacyclics: Honoraria, Research Funding;Roche: Research Funding;Gilead: Research Funding;SOBI: Honoraria;BeiGene: Honoraria;AstraZeneca: Honoraria. Bloor: Novartis: Honoraria;Kite, a Gilead Company: Honoraria. Broom: AbbVie: Honoraria;AstraZeneca: Honoraria;Janssen-Cilag Ltd: Honoraria;Takeda UK Ltd: Honoraria;Celgene Ltd: Honoraria;Gilead: Honoraria. Furtado: Abbvie: Other: Conference support. Morley: Kite: Honoraria;Janssen: Honoraria;AbbVie;Takeda: Other: Conference support;Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Paneesha: Celgene: Honoraria;Roche: Honoraria;Janssen: Honoraria;Gilead: Honoraria;Bristol Myers Squibb: Honoraria;AbbVie: Honoraria. Howard: Roche: Current Employment. Cairns: Merck Sharpe and Dohme: Research Funding;Amgen: Research Funding;Takeda: Research Funding;Celgene / BMS: Other: travel support, Research Funding. Patten: NOVARTIS: Honoraria;ROCHE: Research Funding;JANSSEN: Honoraria;ASTRA ZENECA: Honoraria;ABBVIE: Honoraria;GILEAD SCIENCES: Honoraria, Research Funding. Munir: F. Hoffmann-La Roche: Consultancy;Alexion: Honoraria.

Rheumatology (United Kingdom) ; 60(SUPPL 1):i32-i33, 2021.
Article in English | EMBASE | ID: covidwho-1266154


Background/AimsAlemtuzumab is an efficacious therapy for relapsing remitting multiplesclerosis (RRMS) preventing neural damage and reducing relapse rateby up to 74%. Administered in 2 treatment cycles 12 months apart andauthorised for use in > 40 countries, it is a humanized monoclonalantibody selectively directed against the CD52 antigen of T- and BLymphocytes. Significant autoimmune effects of Alemtuzumab arereported 6-60 months post-treatment including secondary autoimmunity (40%), thyroid disease (18-26%), idiopathic thrombocytopenicpurpura (1-3%) and anti-glomerular basement membrane disease(1%). There are 2 case reports of haemophagocyticlymphohistiocytosis(HLH) in people with MS triggered byAlemtuzumab. HLH is a clinical syndrome of dysregulated, pathological overactivation of innate immunity leading to cytokinestorm, multi-organ failure and a very high mortality rate. Clinicalfeatures are difficult to distinguish from, and may coexist with, othersyndromes such as sepsis. Recognition requires a high index ofclinical suspicion and management through multidisciplinary teams(MDT) using immune suppression. Early recognition and treatmentimprove outcome.MethodsWe report a case of HLH in a 30-year-old female 1 year after her firstcycle of alemtuzumab (second cycle delayed due to COVID-19pandemic) for treatment of RRMS. She was well until presentation 2days post gadolinium-contrasted routine MRI head scan with headache, fever, bacterial pneumonia/empyema and acute kidney injury.Febrile episodes persisted despite antibiotics.ResultsInvestigations revealed hepatosplenomegaly, pancytopenia(Haemoglobin: 80g/L, WBC: 0.9x109/L, neutrophils: 0.67x109/L, lymphocytes: 0.14 X109/L, platelets: 82x109/L), hypertriglyceridaemia(5.5mmol/L) and hyperferritinaemia (94023ng/ml). She fulfilled theHistiocyte Society HLH-2004 diagnostic criteria for HLH (H-score:238). Initial treatment was IV methylprednisolone (1g) and intravenousimmunoglobulin (IVIG) 2g/kg. Ferritin levels initially decreased(66933ng/ml) but re-escalated (93912ng/ml) with clinical deterioration, necessitating additional treatment with subcutaneous Anakinra 4mg/kg(recombinant interleukin-1 receptor antagonist) alongside oralprednisolone 1mg/kg. There was rapid, sustained improvement withresolution of fever but ferritin levels remained highly elevated(45000ng/ml) and cytopaenia was slow to resolve. Marker T cellsubsets showed significant T cell depression presumably postalemtuzumab. MDT discussion locally and nationally through theHLH Across Speciality Collaboration (HASC) led to discharge withcareful outpatient monitoring. Further IVIG 2g/kg was administeredwhich led to complete resolution of HLH and treatment wean.

British Journal of Haematology ; 193(SUPPL 1):173-174, 2021.
Article in English | EMBASE | ID: covidwho-1255357


Content: Introduction: Ibrutinib is a small molecule Bruton's tyrosine kinase (BTK) inhibitor which has revolutionised treatment of chronic lymphocytic leukaemia (CLL). BTK is involved in B-cell receptor signalling regulating normal B-cell activation, interactions and survival. Ibrutinib use can predispose to invasive fungal infections (IFI), via dysregulation of the innate immune system. We report three patients exhibiting central nervous system (CNS) aspergillosis as a complication of Ibrutinib therapy. Case 1: A 73-year-old man diagnosed with TP53-deleted CLL commenced second-line ibrutinib after initial bendamustine therapy. Five months after starting ibrutinib, he presented with confusion and worsening mobility. Ring-enhancing lesions suggestive of cerebral abscesses were identified on CT and were aspirated. Aspirate confirmed Aspergillus fumigatus and he completed a three-month course of voriconazole. Despite successful treatment of IFI, his CLL progressed and alternative chemotherapy was no-longer suitable. He died six months after discharge from pneumonia. Case 2: A 64-year-old woman with CLL diagnosed in 2020 commenced second-line ibrutinib two months after progression through one FCR cycle. Three weeks into cycle three of ibrutinib, at a time of clinical remission, she presented with a one week history of lethargy, confusion and ataxia without fever or lateralising neurological signs. MRI head demonstrated two large ring-enhancing lesions. In view of aspergillosis risk, empirical voriconazole was initiated. Aspergillus fumigatus was isolated following abscess drainage and voriconazole treatment continued with clinical improvement. She remains well three months after discharge and is planned to re-commence ibrutinib. Case 3: A 61-year-old woman with a background of Crohn's disease on long term prednisolone was diagnosed with TP53-mutated CLL in 2005 and commenced ibrutinib in 2020. COVID-19 pneumonitis was diagnosed three months prior to presentation which was treated with dexamethasone (without IL-6 inhibition). In January 2021 she was admitted with a three-week history of worsening headache, visual field defect and pyrexia. MRI imaging indicated cerebral abscess. She underwent drainage and Aspergillus fumigatus was grown. She made good clinical progress with voriconazole, although her admission was complicated by Pneumocystis jirovecii pneumonia. Discussion: CLL is a haematological malignancy with low incidence of IFI. Cerebral aspergillosis is uncommon, even amongst immunosuppressed individuals, however literature reports have indicated an association with ibrutinib. The first two cases had no other clear predisposition for IFI and are likely attributable to ibrutinib. Case 3 had additional risk factors of long-term and acute steroid use. Onset of ibrutinib-induced CNS IFI can occur early in treatment without any other risk factor and presentations may be atypical, such as the absence of fever in Case 1, or with non-specific symptoms as in Case 2. Ring-enhancement on MRI was present in all three cases. Increased awareness of the potential for IFI, particularly CNS infection, in patients taking ibrutinib is crucial with its increasing use. Clinical suspicion is needed for any patient treated with BTK inhibitors presenting with neurological symptoms or undifferentiated fever. Further research is required to determine if the incidence of invasive aspergillosis in ibrutinib recipients warrants routine antifungal prophylaxis.