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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

Richard Houlston and colleagues report results of a genome-wide association study of chronic lymphocytic leukemia. They validate several new susceptibility loci for this disease, including variants near POT1 , TERC and TERT . Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10 −9 ), 4q26 (rs6858698, P = 3.07 × 10 −9 ), 6q25.2 ( IPCEF1 , rs2236256, P = 1.50 × 10 −10 ) and 7q31.33 ( POT1 , rs17246404, P = 3.40 × 10 −8 ). Additionally, we identified a promising association at 5p15.33 ( CLPTM1L , rs31490, P = 1.72 × 10 −7 ) and validated recently reported putative associations at 5p15.33 ( TERT , rs10069690, P = 1.12 × 10 −10 ) and 8q22.3 (rs2511714, P = 2.90 × 10 −9 ). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.

Richard Houlston and colleagues identify common variants at four loci associated with risk of chronic lymphocytic leukemia, including a coding variant in FARP2 on 2q37.3 and a noncoding variant in the region upstream of MYC on 8q24.21. To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2 ; odds ratio (OR) = 1.39; P = 2.11 × 10 −9 ), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 × 10 −10 ), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 × 10 −7 ) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 × 10 −7 ). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1 ; OR = 1.18; P = 3.67 × 10 −6 ) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 × 10 −6 ). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.

A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.

Imatinib mesylate blocks the activity of three protein tyrosine kinases: ABL, KIT, and platelet-derived growth factor receptor β (PDGFRB). These kinases have crucial roles in chronic myelogenous leukemia (ABL), gastrointestinal stromal tumors (KIT), and certain myeloproliferative diseases (PDGFRB). The first two types of neoplasms have been shown to respond to imatinib mesylate. This article reports that in four patients, a myeloproliferative disorder involving a rearranged PDGFRB gene also responded to the drug. The association of leukemia, eosinophilia, and abnormalities of chromosome 12p13 was originally reported by Keene et al. in 1987 1 ; two of the four patients included in that report also had translocations involving chromosome 5q3. Subsequently, Golub et al. 2 showed that the previously described t(5;12)(q31–q33;p13) chromosomal abnormality, characteristic of some cases of chronic myelomonocytic leukemia, was associated with a fusion gene linking TEL (now known as ETV6 ) with platelet-derived growth factor receptor beta ( PDGFRB ). At least 34 cases of chronic myeloproliferative disease associated with a t(5;12)(q31–q33;p13) translocation have now been reported, 3 and the PDGFRB gene is known . . .

Purpose of ReviewTo 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 FindingsImproved 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.SummaryHCLc 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.

Purpose of ReviewThis review summarises the recent advances in knowledge regarding the biology and treatment of prolymphocytic leukaemias.Recent FindingsBoth B-PLL and T-PLL are genetically complex, and the molecular landscape of these diseases has been well characterised recently. Diagnostic criteria for T-PLL have been refined with the publication of the first international consensus criteria, whereas the diagnosis of B-PLL has been thrown into question by the most recent WHO classification. Treatment advances in B-PLL have relied heavily on the advances seen in CLL that have then been extrapolated to B-PLL with just a few case reports to support the use of these targeted inhibitors. Despite increased knowledge of the biology of T-PLL and some elegant pre-clinical models to identify potential treatments, unfortunately, no improvements have been made in the treatment of T-PLL.SummaryUnmet need is a term oft used for many diseases, but this is particularly true for patients with prolymphocytic leukaemias. Ongoing improvements in our understanding of these diseases will hopefully lead to improved therapies in the future.

T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive post-thymic malignancy with poor response to conventional treatment and short survival. It can readily be distinguished from other T-cell leukemias on the basis of the distinctive morphology, immunophenotype, and cytogenetics. Consistent chromosomal translocations involving the T-cell receptor gene and one of two protooncogenes (TCL-1 and MTCP-1) are seen in the majority of cases and are likely to be involved in the pathogenesis of the disorder. The CD52 antigen is expressed at high density on the malignant T-cells and therapy with alemtuzumab, a humanized IgG1 antibody that targets this antigen, has produced promising results. In relapsed/refractory patients overall and complete response rates have been seen in up to 76% and 60%, respectively. In previously untreated patients, complete remission rates of 100% have been reported. These responses are durable and translate into improved survival for responders. However, relapse is inevitable and strategies using both autologous and allogeneic stem cell transplantation are currently being explored. Additional clinical trials are investigating the use of alemtuzumabin combinations with chemotherapy, either concurrent or sequential. In the future we hope to have a betterunderstanding of how best to integrate these therapeutic approaches to further prolong survival for patients with T-PLL.

Alemtuzumab was the first monoclonal antibody to be humanized, a process which embeds rodent sequence fragments in a human IgG framework. The antibody target is CD52, an antigen expressed on normal lymphocytes as well as many T- and B-cell neoplasms. It therefore has a potential broad application across a spectrum of B- and T-cell malignancies as well as use as an immunosuppressant drug in, for example, bone marrow transplantation. The original licensing in the USA and Europe was for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL). However, recent trials using alemtuzumab as a first-line agent for CLL have shown superior response rates compared with traditional alkylator therapy and this has led to US FDA approval for first-line treatment for CLL. It seems to be particularly useful in patients with CLL who have deletion of the TP53 tumor suppressor gene, a subset of disease that responds poorly to other currently available chemotherapeutics.

In this trial, patients with previously treated and relapsed chronic lymphoid leukemia who received ibrutinib had significantly improved progression-free survival, overall survival, and response rate, as compared with those who received ofatumumab. Chronic lymphoid leukemia (CLL) is characterized by a variable natural history that is partly predicted by clinical and genomic features. 1 Therapy for CLL has evolved from monotherapy with alkylating agents to chemoimmunotherapy. 2 , 3 Each of the combination regimens has shown prolonged rates of progression-free survival, as compared with similar regimens that do not contain antibodies. Treatment of patients with relapsed CLL often includes regimens such as bendamustine and rituximab, 4 ofatumumab, 5 or investigational agents. 6 – 8 Ofatumumab was approved by the Food and Drug Administration (FDA) and the European Medicines Agency on the basis of a single-group study involving patients who had . . .