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Abstract 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

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 [ABSTRACT FROM AUTHOR]

Unusual clinical manifestations and associations with auto-immunity or other systemic disorders are uncommon clinical features of hairy cell leukemia (HCL). The exact prevalence of these rare associations is difficult to determine as they are mostly published as anecdotal case reports and generally not included in larger published series. This chapter deals with uncommon clinical manifestations and rare sites of involvement in HCL. It also summarizes the association with systemic hemato-oncological disorders as well as second malignancies, based on review of the relevant literature and from personal experience. [ABSTRACT FROM AUTHOR]

Abstract: Conventional anticancer therapeutics often suffer from lack of specificity, resulting in toxicities to normal healthy tissues and poor therapeutic index. Antibody-mediated delivery of anticancer drugs or toxins to tumor cells through tumor selective or overexpressed antigens is progressively being recognized as an effective strategy for increasing the therapeutic index of anticancer drugs. In this review we focus on three therapeutic modalities in the field of antibody-mediated targeting, including antibody-drug conjugates (ADCs), immunotoxins (ITs) and immunoliposomes (ILs). Design considerations for development of each of the above therapeutic modalities are discussed. Furthermore, an overview of ADCs, ITs or ILs approved for use in clinical oncology and those currently in clinical development is provided. Challenges encountered by the field of antibody-based targeting are discussed and concepts around development of the next generation of antibody therapeutics are presented. [Copyright &y& Elsevier]

Résumé: La leucémie à tricholeucocytes dans sa forme classique (HCL) ou sa forme variante (HCL-V), le lymphome splénique de la zone marginale (SMZL) ou le lymphome diffus de la pulpe rouge de la rate (SRPL) appartiennent à un groupe d’hémopathies malignes caractérisées par la présence sanguine de cellules chevelues. Identifier les cellules chevelues et reconnaître ces hémopathies malignes n’est pas toujours aisé en raison de la présence de nombreuses formes frontières. Ces formes, de diagnostic difficile, nécessitent des explorations exhaustives basées sur les données immunologiques, cytogénétiques et moléculaires. La splénectomie est parfois nécessaire pour affirmer le diagnostic. Pour différencier la HCL des autres entités HCL-V, SMZL ou SRPL, un score immunologique basé sur l’expression de quatre marqueurs CD103, CD11c, CD25 et HC2/CD123) a été proposé. Il est à 3 ou 4 dans la HCL et à 0 ou 1 dans les autres maladies. Pour distinguer le SRPL du SMZL, un autre score basé sur cinq marqueurs (CD11c, CD22, CD76, CD27 et CD38) a été développé. Il est dans le SRPL entre 3 et 5 et dans le SMZL entre 0 et 2. Les délétions en 7q sont présentes dans 20 à 40 % des cas de SMZL et les trisomies 3 sont aussi évocatrices de ce diagnostic. Aucune anomalie récurrente n’est identifiée dans les autres proliférations. Si le profil des gènes des chaînes lourdes des immunoglobulines est muté dans 80 % des cas, l’utilisation de certains IGVH peut aider à établir un diagnostic de certitude et avoir un impact sur le pronostic. Les connaissances physiopathologiques de ces maladies se sont améliorées récemment avec notamment l’identification de la mutation BRAFV600E dans la majorité des HCL. La disponibilité des inhibiteurs de BRAF peut être d’un apport considérable dans la prise en charge de ces patients, notamment chez les patients non ou peu répondeurs aux analogues des purines (PNA). [Copyright &y& Elsevier]

Objective: To look at clinical and hematological presentation as well as treatment outcome of patients with diagnosis of Hairy Cell Leukemia (HCL) in our population. Methodology: All patients diagnosed with HCL by morphological and immunohistochemical methods presenting to Medical Oncology Ward at Hayatabad Medical Complex, Peshawar since August 2008 were included in the study. Results: Out of 7 patients diagnosed with HCL, 6 were male and 1 was female (M:F ratio 6:1). Median age at diagnosis was 44 years. Fever, pallor, palpitations and fatigue were the commonest presenting complaints. Spleenomegaly was noted in all patients (100%). Pancytopenia was noted in all patients at presentation. Five patients were treated with Interferon while 2 were treated with Cladribine. At 18 months of follow-up, one out five patients treated with IFN had relapse while both the patients treated with Cladribine were in complete remission. Conclusion: Our study showed that HCL patients present at a younger age in our region but further studies with larger sample size are required to confirm this. All patients showed a complete response to Interferon and Cladribine with all patients alive at 18 months of follow-up. [ABSTRACT FROM AUTHOR]

This short review deals with the ultrastructural surface architecture of hairy cell leukemia (HCL) compared to other leukemic cells, as seen by scanning electron microscopy (SEM). The development of improved techniques for preparing blood cells for SEM in the 1970s readily enabled these features to be visualized more accurately. This review returns us to the earlier history of SEM, when the surface topography of normal and neoplastic cells was visualized and reported for the first time, in an era before the emergence and use of monoclonal antibodies and flow cytometry, now used routinely to define cells by their immunophenotype. Surface microvilli are characteristic for normal and leukemic lymphoid cells, myelo-monocytic cells lack microvilli and show surface ruffles, while leukemic plasma and myeloma cells and megakaryocytes display large surface blebs. HCL cell surfaces are complex and typically ''hybrid'' in nature, displaying both lymphoid and monocytic features with florid ruffles of varying sizes interspersed with clumps of short microvilli cytoplasm. The surface features of other leukemic cells and photomicrographs of immuno-SEM labeling of cells employing antibodies and colloidal gold, reported more than 20 years ago, are shown. [ABSTRACT FROM AUTHOR]

Unusual clinical manifestations, rare sites of involvement, and associations with other disorders and malignancies occurring in patients with hairy cell leukemia (HCL) are uncommon events encountered in a relatively rare disease. The exact prevalence of these associations is difficult to determine accurately in HCL as they are often anecdotal case reports and not always detailed in all larger series of patients. This short review deals with the unusual clinical manifestations and rare sites of involvement of the disease and lists some of the disorders associated with HCL, based on what has been reported in the literature as well as from personal experience. No attempts are made here to establish the true prevalence of these phenomena and only selected references are included. Some details of the coexistence of HCL with other neoplasias, hematological disorders, and ''paraneoplastic'' autoimmune disorders are provided, while opportunistic infections in HCL, particularly atypical mycobacterial disease, are briefly discussed. For the sake of brevity many of the details are provided in tabular form. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) cells accumulate and proliferate in the spleen and the bone marrow. In these tissue compartments, HCL cells interact with accessory cells, matrix proteins, and various cyctokines, collectively referred to as the ''microenvironment.'' Surface receptors expressed on HCL cells and respective stromal ligands are critical for this cross-talk between HCL cells and the microenvironment. Chemokine receptors, adhesion molecules (integrins, CD44), the B cell antigen receptor (BCR), and CD40, expressed on the HCL cells, are likely to be critical for homing, retention, survival, and expansion of the neoplastic B cells. Some of these pathways are now targeted in first clinical trials in other mature B-cell malignancies. We summarize key aspects of the cellular and molecular interactions between HCL cells and their microenvironment. Also, we outline future prospects for therapeutic targeting of the microenvironment in HCL, focusing on CXCR4 and kinase inhibitors (Syk, Btk, phosphatidylinositol 3-kinase [[PI3K]]) that target B cell receptor signaling. [ABSTRACT FROM AUTHOR]

Simple Summary: Hairy cell leukemia (HCL) is a rare B cell neoplasm that accounts for 2% of B-cell lymphomas. The diagnosis was based on the presence of abnormal lymphoid cells that expressed CD103, CD123, CD25 and CD11c. The aim of this retrospective study was to describe the immunophenotypic profile of HCL and HCL-like disorders using 13 markers and to assess the added value of immunophenotypic row data and unsupervised analysis. We confirmed that the immunological profile alone is not sufficient and that morphologic, phenotypic and molecular data need to be integrated. Hairy cell leukemia (HCL) is characterized by abnormal villous lymphoid cells that express CD103, CD123, CD25 and CD11c. HCL-like disorders, including hairy cell leukemia variant (vHCL) and splenic diffuse red pulp lymphoma (SDRPL), have similar morphologic criteria and a distinct phenotypic and genetic profile. We investigated the immunophenotypic features of a large cohort of 82 patients: 68 classical HCL, 5 vHCL/SDRPL and 9 HCL-like NOS. The HCL immunophenotype was heterogeneous: positive CD5 expression in 7/68 (10%), CD10 in 12/68 (18%), CD38 in 24/67 (36%), CD23 in 22/68 (32%) and CD43 in 19/65 (31%) patients. CD26 was expressed in 35/36 (97%) of HCL patients, none of vHCL/SDRPL and one of seven HCL-like NOS (14%). When adding CD26 to the immunologic HCL scoring system (one point for CD103, CD123, CD25, CD11c and CD26), the specificity was improved, increasing from 78.6% to 100%. We used unsupervised analysis of flow cytometry raw data (median fluorescence, percentage of expression) and the mutational profile of BRAF, MAP2K1 and KLF2. The analysis showed good separation between HCL and vHCL/SDRPL. The HCL score is not sufficient, and the use of unsupervised analysis could be promising to achieve a distinction between HCL and HCL-like disorders. However, these preliminary results have to be confirmed in a further study with a higher number of patients. [ABSTRACT FROM AUTHOR]

We recently reported that resveratrol, a grape-derived polyphenol, in vitro induces the apoptosis of leukemic B-cells and simultaneously inhibits the production of endogenous nitric oxide (NO) through inducible NO synthase (iNOS) down-regulation. The same results were observed in the present study with not only acetate derivatives of polyphenols, particularly the pentaacetate of #x03B5;-viniferin (resveratrol dimer), but also with a synthetic flavone (a diaminomethoxyflavone) in both leukemia B-cell lines and B-cell chronic lymphocytic leukemia (B-CLL) patients’ cells. Moreover, flavopiridol, another flavone already known for its pro-apoptotic properties in B-CLL cells, was also found to down-regulate both iNOS expression and NO production. Thus, inhibition of the NO pathway during apoptosis of leukemia B-cells appears a common mechanism for several compounds belonging to two distinct families of phytoalexins, the flavones and grape-derived polyphenols. [Copyright &y& Elsevier]

The characteristics of the very rare non-treatment-related chronic myeloid leukemia (nTr-CML) cases have never before been analyzed. The literature up to December 2002 was screened using the Medline database to identify cases of Tr-CML and nTr-CML. We considered five cases with nTr-CML identified among 270 newly diagnosed CML at our Department. Our report thus considers nine cases with nTr-CML compared to 77 affected by Tr-CML as a secondary neoplasm. The median age at the appearance of the first tumor was higher in nTr-CML patients compared to that of the Tr-CML group (P<0.0001). The median age at CML diagnosis was significantly higher in the nTr-CML than in the Tr-CML group (P<0.0001). The proportion of hematological malignancies as first tumor type was not different in the two groups (44% in nTr-CML versus 56% in Tr-CML). Our study underlines that nTr-CML as a second malignancy is a rare entity associated with elderly age. [Copyright &y& Elsevier]

A replication defective herpes simplex virus-1 was evaluated as a therapeutic vector. Mantle cell lymphoma (MCL), hairy cell leukemia (HCL), and B-cell chronic lymphocytic leukemia (B-CLL) were chosen because leukemic cells were collectable from peripheral bloods in these diseases. Cells from six MCL, one HCL, and nine B-CLL were infected in vitro with T0Z.1 at 3 multiplicity of infection (MOI). Herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV)-mediated suicide gene therapy showed 14.7% of mean tumor killing against leukemic B-cell malignancies. The mean tumor-killing effects were 8.7 and 17.1% in MCL and B-CLL, respectively. The effect against HCL was 29%. The study indicates that herpes simplex virus (HSV)-based gene therapy might be an effective strategy. [Copyright &y& Elsevier]

It has been suggested that HLA-G antigens may provide tumor cells with an effective immune escape mechanism. So far mostly solid tumors have been analyzed; HLA-G antigen was only exceptionally detected. To further examine HLA-G expression, patients were chosen with different forms of leukemia: AML (25), CML (4), ALL (9), CLL (8), HCL (2) and NHL (3). Using flow cytometry with three HLA-G specific mAbs (87G, 01G and MEM-G/9), western blotting with two specific mAbs (4H84 and MEM-G/1) and RT-PCR, neither HLA-G antigen nor mRNA for any HLA-G isoform was detected. These results strongly suggest that HLA-G antigen is not expressed in freshly isolated human leukemia cells and therefore is not involved in their escape from immune attack. [Copyright &y& Elsevier]