FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2324957072> ?p ?o ?g. }

• W2324957072 endingPage "491" @default.
• W2324957072 startingPage "486" @default.
• W2324957072 abstract "B-cell prolymphocytic leukaemia (B-PLL) is a rare lymphoproliferative disorder representing 1% of lymphocytic leukaemias. The largest clinical trial of B-PLL included only 14 patients treated with pentostatin (Döhner et al, 1993). All other studies are limited to case reports or series of fewer than 10 patients. There are no randomized trials published in B-PLL and it is excluded from all registration studies of B-cell chronic lymphocytic leukaemia (CLL); a related but different disorder. B-PLL presents with characteristic morphological, immunophenotypic, cytogenetic and molecular features. With a median age at diagnosis of 69 years, patients typically present with B symptoms, a marked lymphocytosis, cytopenias, massive splenomegaly and minimal lymphadenopathy. A minority present with an indolent phase, but all typically progress, with a median overall survival (OS) of three years. 13q14, 11q23 and 17p deletions are common when interphase fluorescence-in-situ hybridisation (FISH) is performed (Lens et al, 1999). Mutational analyses describe TP53 mutations in >50% of cases, conferring resistance to conventional immunochemotherapy approaches utilized in CLL and B-PLL (Lens et al, 1999; Dearden, 2012). In the absence of national or international guidelines and clinical trial data, clinicians typically employ fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine-rituximab (BR) induction in TP53-intact patients with allogeneic stem cell transplantation (allo-SCT) consolidation in eligible and chemotherapy-responsive patients (Castagna et al, 2005). For TP53-disrupted B-PLL, alemtuzumab has efficacy but is associated with serious infectious toxicity, particularly in older patients (Chaar & Petruska, 2007). Thus, current options have limited efficacy. The B-cell–receptor signalling pathway plays a critical role in the pathogenesis of CLL, although little is known regarding the relative importance of this pathway in B-PLL (Bernal et al, 2001). This pathway is partly mediated by the activation of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ, also termed PIK3CD) which is highly expressed in lymphoid cells (Herishanu et al, 2011). Idelalisib is a potent, oral, selective small-molecule PI3Kδ inhibitor. Rituximab-idelalisib was superior to rituximab-placebo in relapsed CLL [median progression-free survival (PFS) 5·5 months (rituximab-placebo) versus not-reached (rituximab-idelalisib) in 220 patients; hazard ratio (HR) 0·15; P < 0·001]. Patients receiving rituximab-idelalisib experienced a superior overall response rate (81% vs. 13%; P < 0·001) and OS at 12 months (92% vs. 80%; HR 0·28; P = 0·02) compared to placebo (Furman et al, 2014). Notably, the PFS and OS advantage were maintained in those patients (>40% within the trial) with TP53 abnormalities. To date, there are no published data describing the efficacy of idelalisib-rituximab in B-PLL. Five patients from four hospital trusts in the UK were treated with idelalisib-rituximab as part of a UK-wide compassionate use programme supported by Gilead Pharmaceuticals. Data was retrospectively collected for adverse events, clinical and radiological responses. Rituximab (375 mg/m2) was given 2-weekly (cycle 1–2) and then 4-weekly (cycles 3–6), akin to the well established CLL schedule. Idelalisib 150 mg b.d. was administered continuously with dose interruption and reduction as required for toxicity. Clinical response was ascertained both radiologically and clinically according to institutional practice. No formal radiological protocol for monitoring disease response was mandated, particularly as patients presented with massive, palpable splenomegaly and marked lymphocytosis. Adverse events were reported prospectively to the Gilead safety reporting system. Regular clinical monitoring was performed, including regular complete blood counts and biochemistry. FISH assessment for TP53 deletion was performed in all cases. Sanger sequencing was performed according to published guidelines (Pospisilova et al, 2012) on Patients 1 and 2. All patients presented with a lymphocytosis, anaemia, fatigue and prominent splenomegaly (Table 1). The median time to first treatment was 7 months (range, 3–20 months). One patient received high-dose methylprednisolone prior to idelalisib-rituximab, one received BR and intravenous alemtuzumab; and another subcutaneous alemtuzumab. The others were treatment-naïve. All patients had evidence of TP53-disruption, either by FISH or DNA analysis. Hb 78 g/l WBC 435 × 109/l Lymphocytes 413 × 109/l Platelets 118 × 109/l Hb 105 g/l WBC 251 × 109/l Lymphocytes 244 × 109/l Platelets 92 × 109/l Hb 106 g/l WBC 285 × 109/l Lymphocytes 270 × 109/l Platelet 90 × 109/l Hb 130 g/l WBC 102 × 109/l Lymphocytes 97 × 109/l Platelets 114 × 109/l Hb 105 /l WBC 165 × 109/l Lymphocytes 152 × 109/l Platelets 155 × 109/l Splenomegaly 19 cm Para-aortic lymphadenopathy 36 × 34 mm lung nodule Splenomegaly 18 cm Widespread small volume lymphadenopathy DNA sequencing: c.358_375 + 48del (p.Lys120_Thr125del) mutation in exon 4 of the TP53 gene. Loss of TP53 by FISH [LSI TP53 and ATM enumeration probes (Abbott Molecular)] 17p 13.1 Exon 5 mutation by TP53 Sanger Sequencing. DNA sequencing identified a c.517G>T (p.Val173Leu) mutation in exon 5 of the TP53 gene. Loss of TP53 in 55% of cells in peripheral blood by FISH [LSI TP53 and ATM enumeration probes (Abbott Molecular)] Loss of TP53 in 70% of cells in peripheral blood by FISH No mutational analysis done. Loss of TP53 in 88% of cells in peripheral blood by FISH at start of treatment (Cytocell probe 17p13.1) Loss of TP53 in 62% of cells in bone marrow by FISH at initial diagnosis. No mutational analysis done. Nil previously W+W for 7 months 1. Bendamustine & rituximab 2. Gemcitabine & Cisplatin (for lung adenocarcinoma) 3. Alemtuzumab Nil previously W+W for 12 months At time of writing, the median duration of idelalisib was 6 months (range, 37 d to 10·5 months), with 4 patients continuing on treatment (Table 2). Three patients (Patients 1, 2, 4) completed six cycles of idelalisib-rituximab and experienced a rapid improvement in constitutional and abdominal symptoms. All three patients obtained an objective response with normalization of cytopenias, resolution of lymphocytosis and radiological and/or clinical resolution of prominent splenomegaly. These remissions have been sustained for 6–10·5 months to date. At the time of writing, Patient 3 had died of an unrelated metastatic lung carcinoma after 1 month (37 d) of idelalisib-rituximab. At the time of death, the white blood count (WBC) had fallen from 285 × 109/l to 134 × 109/l. Patient 5 has received 1 month of treatment with an excellent early WBC response (baseline: 164 × 109/l, peak: 320 × 109/l at 7 d, 28 d: 112 × 109/l), reduction in palpable splenomegaly and complete symptom resolution. Treatment is on-going in 4 of the 5 patients. Grade 3 Raised ALT in Cycle 2: resolved following dose short interruption and then reduction to 100 mg bd. Grade 2 Skin Rash in Cycle 3, no further dose reduction. Dose increased to 150 mg bd again at end of induction. Grade 3 diarrhoea in Cycle 7 due to biopsy-proven cytomegalovirus (CMV)-induced colitis: idelalisib held, budesonide started followed by 1 mg/kg oral prednisolone initially. Valganciclovir started and prednisolone rapidly weaned. Grade 2 drug-induced organising pneumonia (normal FVC, TLCO 54%). Treated with 1 mg/kg prednisolone concurrently for pneumonitis and colitis, then also valganciclovir. Grade 1 Raised ALT following re-challenge at 100 mg b.d at cycle 10 Grade 2 Raised ALT in Cycle 1, resolved following dose short interruption and then reduction to 100 mg bd. Grade 3 Raised ALT in Cycle 2 resolved following two-week dose interruption. Restarted on alternate day 100 mg od. Recurrent grade 2 raised ALT on 100 mg od alternate days in Cycle 3, resolved therefore increased to 100 mg od daily. Increase to 150 mg from Cycle 4 onwards August 2015 on treatment 3 months: Clinical CR. Normal FBC Early initial response. WBC decreased from 164 × 109/l to 112 × 109/l. Peak 320 × 109/l after 7 d Three patients (1, 2, 4) required early dose interruption and reduction for grade 2–3 transaminitis. This resolved in two patients (1, 4) enabling re-introduction of full dose idelalisib. The third patient (2) required further dose reduction due to recurrent transaminitis. Patient 1 required temporary interruption, initial prednisolone therapy and subsequent valganciclovir for cytomegalovirus (CMV) disease (biopsy-proven CMV colitis (grade 3 diarrhoea) and concurrent grade 2 drug-induced organizing pneumonia and CMV PCR 6·35 × 105/ml). The patient's symptoms quickly resolved on the initiation of valganciclovir and she was rapidly weaned off steroids. The patient restarted idelalisib at 100 mg b.d. and remains on treatment at 10·5 months. CMV reactivation has not been described with idelalisib-rituximab in published trials. This might have resulted from underlying secondary immune-suppression in B-PLL and prior methylprednisolone in this patient. We observed rapid and clinically meaningful responses in TP53-disrupted B-PLL patients treated with idelalisib-rituximab. Responses were relatively durable in the patients treated to date for >6 months. Our experience suggests that this novel approach has promising therapeutic potential in TP53-disrupted B-PLL. A potential role as a bridge to allo-SCT appears appealing. Our experience suggests that a similar toxicity profile exists in the B-PLL setting to that already described in CLL, although further vigilance is needed to assess the relative significance of the isolated case of CMV disease noted in this unique setting. Our data supports the initiation of large observational studies or registries to further evaluate targeted agents in B-PLL. The team would like to thank all the patients involved in the study and the nursing staff who cared for them. TE is funded by the Julian Starmer-Smith Lymphoma Fund. AS is supported by the NIHR Biomedical Research Centre (Oxford). The views expressed are those of the authors and not necessarily those of the Department of Health. TE and AS designed the study; TE co-ordinated the collection of the data. TE wrote the manuscript, which all authors critically reviewed. TE, AS, CF, RW and PS managed the patients in the study and provided data and analysis for the study. TE, CF and AS have received speaker fees and travel expenses from Gilead. CF and AS have received consultancy honoraria. The remaining authors declare no competing financial interests." @default.
• W2324957072 created "2016-06-24" @default.
• W2324957072 creator A5044690250 @default.
• W2324957072 creator A5053298824 @default.
• W2324957072 creator A5066232993 @default.
• W2324957072 creator A5074839524 @default.
• W2324957072 creator A5082526059 @default.
• W2324957072 date "2016-04-07" @default.
• W2324957072 modified "2023-10-16" @default.
• W2324957072 title "Idelalisib-Rituximab induces clinical remissions in patients with TP53 disrupted B cell prolymphocytic leukaemia" @default.
• W2324957072 cites W1979127734 @default.
• W2324957072 cites W1980260104 @default.
• W2324957072 cites W1997202555 @default.
• W2324957072 cites W2019655196 @default.
• W2324957072 cites W2028576612 @default.
• W2324957072 cites W2066027952 @default.
• W2324957072 cites W2066564017 @default.
• W2324957072 cites W2066705204 @default.
• W2324957072 cites W2097778142 @default.
• W2324957072 cites W2318327698 @default.
• W2324957072 doi "https://doi.org/10.1111/bjh.14066" @default.
• W2324957072 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27061924" @default.
• W2324957072 hasPublicationYear "2016" @default.
• W2324957072 type Work @default.
• W2324957072 sameAs 2324957072 @default.
• W2324957072 citedByCount "12" @default.
• W2324957072 countsByYear W23249570722017 @default.
• W2324957072 countsByYear W23249570722018 @default.
• W2324957072 countsByYear W23249570722019 @default.
• W2324957072 countsByYear W23249570722020 @default.
• W2324957072 countsByYear W23249570722021 @default.
• W2324957072 countsByYear W23249570722022 @default.
• W2324957072 crossrefType "journal-article" @default.
• W2324957072 hasAuthorship W2324957072A5044690250 @default.
• W2324957072 hasAuthorship W2324957072A5053298824 @default.
• W2324957072 hasAuthorship W2324957072A5066232993 @default.
• W2324957072 hasAuthorship W2324957072A5074839524 @default.
• W2324957072 hasAuthorship W2324957072A5082526059 @default.
• W2324957072 hasBestOaLocation W23249570721 @default.
• W2324957072 hasConcept C126322002 @default.
• W2324957072 hasConcept C143998085 @default.
• W2324957072 hasConcept C203014093 @default.
• W2324957072 hasConcept C2775983024 @default.
• W2324957072 hasConcept C2777938653 @default.
• W2324957072 hasConcept C2778461978 @default.
• W2324957072 hasConcept C2779260929 @default.
• W2324957072 hasConcept C2779338263 @default.
• W2324957072 hasConcept C2779878957 @default.
• W2324957072 hasConcept C2780653079 @default.
• W2324957072 hasConcept C502942594 @default.
• W2324957072 hasConcept C71924100 @default.
• W2324957072 hasConceptScore W2324957072C126322002 @default.
• W2324957072 hasConceptScore W2324957072C143998085 @default.
• W2324957072 hasConceptScore W2324957072C203014093 @default.
• W2324957072 hasConceptScore W2324957072C2775983024 @default.
• W2324957072 hasConceptScore W2324957072C2777938653 @default.
• W2324957072 hasConceptScore W2324957072C2778461978 @default.
• W2324957072 hasConceptScore W2324957072C2779260929 @default.
• W2324957072 hasConceptScore W2324957072C2779338263 @default.
• W2324957072 hasConceptScore W2324957072C2779878957 @default.
• W2324957072 hasConceptScore W2324957072C2780653079 @default.
• W2324957072 hasConceptScore W2324957072C502942594 @default.
• W2324957072 hasConceptScore W2324957072C71924100 @default.
• W2324957072 hasIssue "3" @default.
• W2324957072 hasLocation W23249570721 @default.
• W2324957072 hasLocation W23249570722 @default.
• W2324957072 hasOpenAccess W2324957072 @default.
• W2324957072 hasPrimaryLocation W23249570721 @default.
• W2324957072 hasRelatedWork W1857647970 @default.
• W2324957072 hasRelatedWork W1935352059 @default.
• W2324957072 hasRelatedWork W2256822827 @default.
• W2324957072 hasRelatedWork W2284358343 @default.
• W2324957072 hasRelatedWork W2603731451 @default.
• W2324957072 hasRelatedWork W2742028700 @default.
• W2324957072 hasRelatedWork W2914122763 @default.
• W2324957072 hasRelatedWork W3041858987 @default.
• W2324957072 hasRelatedWork W4246239471 @default.
• W2324957072 hasRelatedWork W4385740334 @default.
• W2324957072 hasVolume "177" @default.
• W2324957072 isParatext "false" @default.
• W2324957072 isRetracted "false" @default.
• W2324957072 magId "2324957072" @default.
• W2324957072 workType "article" @default.