Publications by authors named "Claire Dearden"

109 Publications

Hairy cell leukemia and COVID-19 adaptation of treatment guidelines.

Leukemia 2021 07 4;35(7):1864-1872. Epub 2021 May 4.

Haematology Department, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.
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http://dx.doi.org/10.1038/s41375-021-01257-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093591PMC
July 2021

Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial.

J Hematol Oncol 2021 02 24;14(1):35. Epub 2021 Feb 24.

Developmental Therapeutics Consortium, 175 E Delaware Pl #7204, Chicago, IL, USA.

Background: Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL).

Methods: Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days.

Results: Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26-48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3-4 events; these events were generally reversible. No treatment-related deaths were reported.

Conclusions: Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy.

Trial Registration: ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://clinicaltrials.gov/ct2/show/NCT01829711.
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http://dx.doi.org/10.1186/s13045-020-01004-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905554PMC
February 2021

TCL1 and TCR collaborate to drive T-PLL.

Authors:
Claire Dearden

Blood 2020 12;136(24):2723-2724

The Royal Marsden Hospital.

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http://dx.doi.org/10.1182/blood.2020008922DOI Listing
December 2020

Hairy Cell Leukaemia: From Hairy Beginnings to a BRAF New World.

Br J Haematol 2020 11;191(4):527-534

The Royal Marsden Hospital and the Institute of Cancer Research, Biomedical Research Centre, Sutton, UK.

For a disease initially described in 1958 as a leukaemic reticulo-endotheliosis associated with poor outcomes, we have come a long way in our understanding of Hairy cell leukaemia. The vast majority of patients diagnosed with this rare, often diagnostically challenging, leukaemia can now expect a lifespan that is similar to the general population. This article covers some of the highlights from the last 6 decades that have led to our current understanding of this fascinating leukaemia - from elucidation of its B-cell origin to discovery of the almost universal occurrence of the BRAF V600E mutation; from the initial successes reported with splenectomy to the more recent development of targeted therapies such as Vemurafenib and Moxetumomab Pasudotox. It also pays tribute to some of the outstanding research in this field focusing particularly on the significant contributions made by the clinical and scientific community in the UK.
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http://dx.doi.org/10.1111/bjh.17158DOI Listing
November 2020

Controversies in the Treatment of Peripheral T-cell Lymphoma.

Hemasphere 2020 Oct 1;4(5):e461. Epub 2020 Sep 1.

Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.

Peripheral T-cell lymphomas are a heterogeneous group of rare diseases with an aggressive behavior and dismal prognosis. Their classification is complex and still evolving, and several biomolecular markers now help refine the prognosis of specific disease entities, although still have limited impact in tailoring the treatment. First-line treatment strategies can cure only a minority of patients and relapsed-refractory disease still represents the major cause of failure. Frontline autologous transplantation may have an impact in the consolidation of response; however, its role is still questioned as far as complete responses obtained after induction chemotherapy are concerned. Newer drugs are now being evaluated in clinical trials, but effective salvage strategies for those who experience treatment failures are lacking. Here we review and discuss the most controversial aspects of diagnosis and treatment of peripheral T-cell lymphomas.
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http://dx.doi.org/10.1097/HS9.0000000000000461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469987PMC
October 2020

Guideline for diagnosis and management of hairy cell leukaemia (HCL) and hairy cell variant (HCL-V).

Br J Haematol 2020 12 14;191(5):730-737. Epub 2020 Oct 14.

Department of Haematology, Royal Marsden NHS Trust, London, UK.

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http://dx.doi.org/10.1111/bjh.17055DOI Listing
December 2020

Hairy Cell Leukaemia.

Curr Oncol Rep 2020 04 16;22(5):42. Epub 2020 Apr 16.

The Royal Marsden Hospital and the Institute of Cancer Research, Sutton, UK.

Purpose Of Review: To summarise diagnostic clinical/laboratory findings and highlight differences between classical hairy cell leukaemia (HCLc) and hairy cell leukaemia variant (HCLv). Discussion of prognosis and current treatment indications including novel therapies, linked to understanding of the underlying molecular pathogenesis.

Recent Findings: Improved understanding of the underlying pathogenesis of HCLc, particularly the causative mutation BRAF V600E, leading to constitutive activation of the MEK/ERK signalling pathway and increased cell proliferation. HCLc is caused by BRAF V600E mutation in most cases. Purine nucleoside analogue (PNA) therapy is the mainstay of treatment, with the addition of rituximab, improving response and minimal residual disease (MRD) clearance. Despite excellent responses to PNAs, many patients will eventually relapse, requiring further therapy. Rarely, patients are refractory to PNA therapy. In relapsed/refractory patients, novel targeted therapies include BRAF inhibitors (BRAFi), anti-CD22 immunoconjugate moxetumomab and Bruton tyrosine kinase inhibitors (BTKi). HCLv has a worse prognosis with median overall survival (OS), only 7-9 years, despite the combination of PNA/rituximab improving front-line response. Moxetumomab or ibrutinib may be a viable treatment but lacks substantial evidence.
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http://dx.doi.org/10.1007/s11912-020-00911-0DOI Listing
April 2020

Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia.

Blood 2019 10 10;134(14):1132-1143. Epub 2019 Jul 10.

The Royal Marsden Hospital, NHS Foundation Trust, London, United Kingdom.

T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm with a heterogeneous clinical course. With the advent of novel treatment options that will potentially change the management of patients with T-PLL, it has become necessary to produce consensus guidelines for the design and conduct of clinical trials. The T-PLL International Study group (TPLL-ISG) set out to define standardized criteria for diagnosis, treatment indication, and evaluation of response. These criteria will facilitate comparison of results from clinical trials in T-PLL, and will thus support clinical decision making, as well as the approval of new therapeutics by healthcare authorities.
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http://dx.doi.org/10.1182/blood.2019000402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042666PMC
October 2019

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

Blood Cancer J 2018 12 21;9(1). Epub 2018 Dec 21.

German Cancer Research Center, 69120, Heidelberg, Germany.

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
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http://dx.doi.org/10.1038/s41408-018-0162-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315026PMC
December 2018

Improvement in Parameters of Hematologic and Immunologic Function and Patient Well-being in the Phase III RESONATE Study of Ibrutinib Versus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Clin Lymphoma Myeloma Leuk 2018 12 18;18(12):803-813.e7. Epub 2018 Aug 18.

The Leeds Teaching Hospitals, St. James University Hospital, Leeds, United Kingdom.

Background: Ibrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Patients And Methods: Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization.

Results: With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P < .0001). Higher rates of clinically meaningful improvement were demonstrated with ibrutinib versus ofatumumab for FACIT-F and EORTC global health. Greater improvement was observed in disease-related weight loss, fatigue, night sweats, and abdominal discomfort with ibrutinib versus ofatumumab. Hospitalizations in the first 30 days occurred less frequently with ibrutinib than ofatumumab (0.087 vs. 0.184 events/patient; P = .0198). New-onset diarrhea was infrequent with ibrutinib after the first 6 months (47% at ≤6 months vs. 5% at 12-18 months). With ibrutinib, grade ≥ 3 hypertension occurred in 6%, grade ≥ 3 atrial fibrillation in 4%, major hemorrhage in 2%, and tumor lysis syndrome in 1% of patients.

Conclusion: Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL.
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http://dx.doi.org/10.1016/j.clml.2018.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527106PMC
December 2018

Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia.

Leukemia 2018 08 20;32(8):1768-1777. Epub 2018 Jul 20.

City of Hope National Medical Center, Duarte, CA, USA.

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.
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http://dx.doi.org/10.1038/s41375-018-0210-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087717PMC
August 2018

Outcomes following front-line chemotherapy in peripheral T-cell lymphoma: 10-year experience at The Royal Marsden and The Christie Hospital.

Leuk Lymphoma 2018 07 9;59(7):1586-1595. Epub 2017 Nov 9.

b The University of Manchester and The Christie NHS Foundation Trust, Manchester Academic Health Science Centre , Manchester , UK.

We evaluated the outcomes for patients with peripheral T-cell lymphoma (PTCL) undergoing front-line chemotherapy at our institutions between 2002 and 2012. One hundred and fifty-six patients were eligible, comprising PTCL not otherwise specified (NOS) (n = 50, 32.0%), angioimmunoblastic T-cell lymphoma (AITL) (n = 44, 28.2%), anaplastic large-cell lymphoma (ALCL) ALK negative (n = 23, 14.7%), ALCL ALK positive (n = 16, 10.3%), and other (n = 23, 14.7%). Most patients received CHOP (66.0%) and 13.0% received an autologous hematopoietic progenitor cell transplant (HPCT). With a median follow-up of 63.4 months, 5-year overall survival (OS) and progression-free survival (PFS) was 38.8% and 19.8% respectively. Independent risk factors for inferior OS were age >60 years, International Prognostic Index (IPI) ≥ 2 and lack of complete response to induction. When responding patients were compared by receipt of an autologous HPCT versus not, HPCT was associated with improved PFS (p = .001) and OS (p = .046) and remained significant for PFS in multivariate analysis suggesting a possible therapeutic benefit.
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http://dx.doi.org/10.1080/10428194.2017.1393671DOI Listing
July 2018

Haemophagocytic lymphohistiocytosis as a consequence of untreated B-cell chronic lymphocytic leukaemia.

BMJ Case Rep 2017 Apr 26;2017. Epub 2017 Apr 26.

Department of Haematology, UCLH, London, UK.

Haemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome characterised by defective cytotoxic function and hypercytokinaemia leading to macrophage expansion and haemophagocytosis. Patients often present with unexplained fevers, hepatosplenomegaly and pancytopenia, with elevation in serum ferritin and triglyceride. Acquired forms are triggered by infection, malignancy or rheumatological disorders. HLH in the setting of chronic lymphocytic leukaemia is rarely reported, however, and is usually associated with infection or as a consequence of chemotherapy. We present a case of HLH in a 64-year-old Caucasian woman with the only identified trigger being her hitherto untreated CLL.
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http://dx.doi.org/10.1136/bcr-2016-219057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534911PMC
April 2017

Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL.

Blood 2017 05 3;129(19):2612-2615. Epub 2017 Apr 3.

The Ohio State University Medical Center, The Ohio State University, Columbus, OH.

Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE trial. The overall mean dose intensity (DI) was 95% with median treatment duration of ∼9 months. Pharmacokinetic assessment of ibrutinib exposure at 420-mg dose suggested similar exposure regardless of patient weight or age. As assessed by independent review committee, patients with higher DI experienced longer median progression-free survival (PFS) compared with those with lower DI regardless of del17p and/or status. Of 79 patients requiring a drug hold, treatment was restarted at the original dose in 73 (92%) patients. Mean duration of a missed-dose event was 18.7 days (range, 8-56). Patients missing ≥8 consecutive days of ibrutinib had a shorter median PFS vs those missing <8 days (10.9 months vs not reached). These results support sustained adherence to once-daily ibrutinib dosing at 420 mg as clinically feasible to achieve optimal outcomes in patients with previously treated CLL. The trial was registered at www.clinicaltrials.gov as #NCT01578707.
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http://dx.doi.org/10.1182/blood-2016-12-737346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437732PMC
May 2017

T-cell Prolymphocytic Leukemia.

Hematol Oncol Clin North Am 2017 04;31(2):273-283

Department of Haemato-Oncology, The Royal Marsden Biomedical Research Centre, London, UK; Department of Haemato-Oncology, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Electronic address:

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-cell malignancy. T-PLL can be distinguished from other lymphoid diseases by the evaluation and integration of clinical features, morphology, immunophenotyping, cytogenetics, and molecular features. The current therapeutic approach relies on immunotherapy followed by a hematopoietic stem cell transplant in selected cases. Clinical outcomes are generally poor, although insights from genomic and molecular studies may increase our understanding of this disease, with the promise of additional effective therapeutic options.
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http://dx.doi.org/10.1016/j.hoc.2016.11.010DOI Listing
April 2017

Epidemiology and environmental aspects of marginal zone lymphomas.

Best Pract Res Clin Haematol 2017 Mar - Jun;30(1-2):84-91. Epub 2016 Nov 5.

Department of Haemato-Oncology, Royal Marsden Hospital NHS Foundation Trust, Downs Road, Sutton, UK. Electronic address:

Marginal zone lymphomas (MZLs) account for between 5% and 17% of all non-Hodgkin's lymphomas. MZLs consist of 3 different subtypes with extranodal being the most commonly reported, representing 50-70% of MZL, followed by splenic (20%) and nodal (10%). Median age at presentation varies between these lymphoma sub-types, ranging between 50 and 69 years, with an overall greater incidence noted in males compared to females. Given the rarity of these lymphomas, epidemiologic data has been sparse, although it has been suggested the aetiology is multi-factorial including ethnicity and geographical factors. Other reported associations include autoimmune disease and infection, with Helicobacter pylori and Campylobacter psittaci, being the most commonly reported pathogens. Larger population studies are required to investigate the role of these environmental factors further as these can direct the future management of these lymphomas, through the use of more effective targeted treatments.
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http://dx.doi.org/10.1016/j.beha.2016.07.002DOI Listing
October 2017

Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.

Nat Commun 2017 02 6;8:14175. Epub 2017 Feb 6.

Department of Haematology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10), 1q42.13 (rs41271473, P=1.06 × 10), 4q24 (rs71597109, P=1.37 × 10), 4q35.1 (rs57214277, P=3.69 × 10), 6p21.31 (rs3800461, P=1.97 × 10), 11q23.2 (rs61904987, P=2.64 × 10), 18q21.1 (rs1036935, P=3.27 × 10), 19p13.3 (rs7254272, P=4.67 × 10) and 22q13.33 (rs140522, P=2.70 × 10). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.
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http://dx.doi.org/10.1038/ncomms14175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303820PMC
February 2017

Eradication of minimal residual disease improves overall and progression-free survival in patients with chronic lymphocytic leukaemia, evidence from NCRN CLL207: a phase II trial assessing alemtuzumab consolidation.

Br J Haematol 2017 02 29;176(4):573-582. Epub 2016 Dec 29.

Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

With immunochemotherapy, remission duration and survival in patients with chronic lymphocytic leukaemia is dependent on the level of minimal residual disease (MRD) after treatment. This phase II trial assessed alemtuzumab consolidation post-chemotherapy in patients who responded with persistent low levels of detectable disease. Blood was screened for MRD using multi-parameter flow cytometry, 6-24 months post-chemotherapy. MRD-positive participants received alemtuzumab 30 mg subcutaneously 3 times weekly for 6 weeks. Following a marrow assessment, MRD-negative participants or non-responders stopped therapy and MRD-positive participants with 1 + log reduction had 6 more weeks of alemtuzumab. Alemtuzumab consolidation was received by 47 participants. One death and 19 of 22 serious adverse events reported from 17 (36%) participants were alemtuzumab-related. MRD eradication from blood and bone marrow was achieved in 39 (83%) participants at the end of consolidation, with 18 (38%) remaining MRD-negative in the blood 6 months later. Of the 18 participants who were MRD-negative at 6 months, the median time to MRD relapse was 46 months, which was similar to patients who were MRD-negative at baseline and were followed up. The 5-year progression-free survival (PFS) and overall survival (OS) of participants who were MRD-negative at 6 months was significantly better than MRD-positive participants [PFS: 78% vs. 39% (P = 0·010), OS: 89% vs. 64% (P = 0·029)].
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http://dx.doi.org/10.1111/bjh.14342DOI Listing
February 2017

Outcomes for transformed follicular lymphoma in the rituximab era: the Royal Marsden experience 2003-2013.

Leuk Lymphoma 2017 08 8;58(8):1805-1813. Epub 2016 Dec 8.

a The Royal Marsden Hospital, London and Surrey , United Kingdom.

Survival for transformed follicular lymphoma (tFL) has improved in the rituximab era and the need for upfront stem cell transplantation (SCT) is unclear. We evaluated the outcomes for all patients treated with first-line chemotherapy for histologically-proven tFL at our institution from 2003-2013 (n = 87). The majority of patients (89.7%) did not receive a SCT as part of first-line management. With a median follow-up of 7.8 years the 5-year overall survival (OS) for all patients was 61.7%. Patients treated with R-CHOP without upfront SCT (n = 55/87) had a 5-year OS of 64.3%. In a Cox regression analysis of the entire cohort (n = 87) International Prognostic Index (IPI) risk group and presence of B symptoms at transformation were independently associated with OS in multivariate analysis (MVA). Our analysis confirms the improved survival of tFL in the rituximab era even in the absence of upfront SCT consolidation.
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http://dx.doi.org/10.1080/10428194.2016.1265114DOI Listing
August 2017

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia.

Blood 2017 02 30;129(5):553-560. Epub 2016 Nov 30.

Department of Hematology, Medical University of Lodz, Lodz, Poland.

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.
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http://dx.doi.org/10.1182/blood-2016-01-689422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290982PMC
February 2017

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.

Blood 2016 11 15;128(19):2319-2326. Epub 2016 Aug 15.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.

Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 () co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL ( = .009). This study further highlights telomere dysregulation as a key process in CLL development.
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http://dx.doi.org/10.1182/blood-2016-01-695692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271173PMC
November 2016

BRAF inhibition in hairy cell leukemia with low-dose vemurafenib.

Blood 2016 06 3;127(23):2847-55. Epub 2016 Mar 3.

Department of Medicine V, University of Heidelberg, Heidelberg, Germany; Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany;

The activating mutation of the BRAF serine/threonine protein kinase (BRAF V600E) is the key driver mutation in hairy cell leukemia (HCL), suggesting opportunities for therapeutic targeting. We analyzed the course of 21 HCL patients treated with vemurafenib outside of trials with individual dosing regimens (240-1920 mg/d; median treatment duration, 90 days). Vemurafenib treatment improved blood counts in all patients, with platelets, neutrophils, and hemoglobin recovering within 28, 43, and 55 days (median), respectively. Complete remission was achieved in 40% (6/15 of evaluable patients) and median event-free survival was 17 months. Response rate and kinetics of response were independent of vemurafenib dosing. Retreatment with vemurafenib led to similar response patterns (n = 6). Pharmacodynamic analysis of BRAF V600E downstream targets showed that vemurafenib (480 mg/d) completely abrogated extracellular signal-regulated kinase phosphorylation of hairy cells in vivo. Typical side effects also occurred at low dosing regimens. We observed the development of acute myeloid lymphoma (AML) subtype M6 in 1 patient, and the course suggested disease acceleration triggered by vemurafenib. The phosphatidylinositol 3-kinase hotspot mutation (E545K) was identified in the AML clone, providing a potential novel mechanism for paradoxical BRAF activation. These data provide proof of dependence of HCL on active BRAF signaling. We provide evidence that antitumor and side effects are observed with 480 mg vemurafenib, suggesting that dosing regimens in BRAF-driven cancers could warrant reassessment in trials with implications for cost of cancer care.
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http://dx.doi.org/10.1182/blood-2015-11-680074DOI Listing
June 2016

Interesting case of lymphocytosis and splenomegaly.

BMJ 2016 Mar 3;352:i1227. Epub 2016 Mar 3.

Department of Haemato-Oncology, Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK.

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http://dx.doi.org/10.1136/bmj.i1227DOI Listing
March 2016

Management of prolymphocytic leukemia.

Authors:
Claire Dearden

Hematology Am Soc Hematol Educ Program 2015 ;2015:361-7

Department of Haemato-Oncology, Royal Marsden Biomedical Research Centre, London, UK.

B-cell (B-PLL) and T-cell (T-PLL) prolymphocytic leukemias are rare, poor-prognosis lymphoid neoplasms with similar presentation characterized by symptomatic splenomegaly and lymphocytosis. They can be distinguished from each other and from other T- and B-cell leukemias by careful evaluation of morphology, immunophenotyping, and molecular genetics. The clinical behavior is typically aggressive, although a subset of patients may have an indolent phase of variable length. First-line therapy for T-PLL is with intravenous alemtuzumab and for B-PLL is with combination purine analog-based chemo-immunotherapy. New B-cell receptor inhibitors, such as ibrutinib and idelalisib, may have a role in the management of B-PLL, especially for the patients harboring abnormalities of TP53. Allogenic stem cell transplantation should still be considered for eligible patients and may be the only current therapy capable of delivering a cure. In the past few years, many of the molecular mechanisms underlying disease pathogenesis and progression have been revealed and are likely to lead to the development of novel targeted approaches.
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http://dx.doi.org/10.1182/asheducation-2015.1.361DOI Listing
October 2016

Long-term follow-up after purine analogue therapy in hairy cell leukaemia.

Best Pract Res Clin Haematol 2015 Dec 9;28(4):217-29. Epub 2015 Oct 9.

Division of Molecular Pathology, The Institute of Cancer Research, London, UK. Electronic address:

Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL. Although they have not been compared in randomised trials, they appear to be equally effective. A complete response is important for the long-term outcome and we look at how best this can be achieved. Evidence is emerging which supports the use of either purine analogue plus an anti-CD20 monoclonal antibody after relapse, though questions remain concerning the scheduling of the monoclonal antibody. Patients refractory to the purine analogues may require alternative agents.
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http://dx.doi.org/10.1016/j.beha.2015.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509559PMC
December 2015
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