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Background: Hairy cell leukemia (HCL) is rare leukemia of mature B cells, accounting for 2% of all lymphoid neoplasms. Although the association of venous thromboembolism (VTE) with cancer is well established, there is no systematic study describing VTE in HCL. Aim: To analyze prevalence and risk factors associated with VTE in HCL patients. Methods: We retrospectively reviewed data from the medical records of 56 consecutive HCL patients evaluated in our Hematology/Oncology clinic between 1998 and 2023. Results: The median age at diagnosis was 59 years (range, 37–94), and 49 patients (87%) were male. With a median follow-up of 122 months (1–291), we identified 11 episodes of VTE in 8 (14%) HCL patients: pulmonary embolism (PE) (5 cases) with or without concurrent deep venous thrombosis (DVT), and DVT alone (6 cases). All thrombotic episodes occurred after the diagnosis of HCL, or at the same time of it, as presenting clinical manifestation of the HCL. Risk factors for VTE other than cancer were identified in only 3 patients. Conclusion: Our study found a high incidence of VTE in patients with HCL, mostly in the absence of other provoking factors, suggesting that this hematologic malignancy is associated with an underlying thrombophilic state. [ABSTRACT FROM AUTHOR]

We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40–18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings. [ABSTRACT FROM AUTHOR]

The presence of BRAF mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains largely understudied. This research aims to evaluate patient characteristics and outcomes of BRAF-mutated MNs. Among a cohort of 6667 patients, 48 (0.7%) had BRAF-mutated MNs. Notably, three patients exhibited sole BRAF mutation, providing evidence supporting the hypothesis of BRAF's role as a driver mutation in MNs. In acute myeloid leukemia, the majority of patients had secondary acute myeloid leukemia, accompanied by poor-risk cytogenic and RAS pathway mutations. Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant. [ABSTRACT FROM AUTHOR]

Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is a rare type of lymphoma that affects the spleen, bone marrow, and peripheral blood. It was initially thought to be a variant of splenic marginal zone lymphoma (SMZL) but is now recognized as a separate entity. SDRPL is difficult to diagnose based on peripheral blood and bone marrow samples alone, and a splenectomy is often necessary for an accurate diagnosis. The pathogenesis of SDRPL is not well understood, but it is associated with specific genetic changes, including mutations in BCOR, CCND3, NOTCH pathway genes, and MAP2K1. The prognosis and treatment response of SDRPL vary, but TP53 inactivation, through mutation and/or deletion, is associated with an aggressive clinical course. [Extracted from the article]

Hairy cell leukemia (HCL) is a rare type of leukemia that primarily affects men and is characterized by abnormal B cells with cytoplasmic projections. The standard treatment for HCL has been purine analogs, which have shown high response rates but also carry risks of immunosuppression and disease relapse. Recent studies have explored the use of rituximab in combination with purine analogs, showing promising results in relapsed HCL patients. Additionally, a study from the MD Anderson group demonstrated the efficacy and safety of sequential cladribine followed by rituximab as a first-line therapy for HCL. The role of measurable residual disease (MRD) as a predictor of treatment response and remission duration is still being investigated. Furthermore, the use of the BRAF inhibitor vemurafenib in combination with obinutuzumab has shown promising results in previously untreated HCL patients. Overall, these findings suggest that chemo-immunotherapy may be a more effective standard of care for HCL, and future research should focus on refining treatment protocols and exploring other treatment options. [Extracted from the article]

This letter to the editor discusses the case of a 47-year-old woman with relapsed/refractory hairy cell leukemia (cHCL) who achieved complete remission (CR) following treatment with the bispecific antibody mosunetuzumab. The patient had previously undergone various treatments, including cladribine, pentostatin, rituximab, vemurafenib, and moxetumomab pasudotox, but experienced relapse or insufficient response. Mosunetuzumab therapy resulted in hematologic CR for at least nine months, with negative measurable residual disease (MRD) based on blood tests. The use of bispecific antibodies in the treatment of cHCL shows promise and warrants further investigation. [Extracted from the article]

The letter to the editor responds to a recent paper by Hardell and colleagues that investigated the risks of non-Hodgkin lymphoma (NHL) and hairy cell leukemia following exposure to glyphosate and phenoxyacetic acid herbicides. The authors of the letter argue that the methodological approaches used by Hardell et al. introduced bias and limitations that impacted the validity of their findings. They highlight concerns about recall bias, the construction of the reference group, small sample sizes, regression methods, and participation rates. The authors disagree with Hardell et al.'s conclusions and suggest that cohort studies provide more reliable evidence on the risks of glyphosate exposure and NHL. [Extracted from the article]

The association between pesticide exposure and non-Hodgkin lymphoma (NHL) including hairy cell leukemia (HCL) was analyzed in a pooled study of three case-control studies. Results on exposure to pesticides were based on 1,425 cases and 2,157 controls participating in the studies. Exposures were assessed by self-administered questionnaires completed as needed by phone. In the pooled univariate analyses adjusted by age, gender and year of diagnosis, exposure to herbicides of the phenoxyacetic acid type yielded statistically significant increased risk with odds ratio (OR) = 1.9, 95% confidence interval CI) = 1.4–2.5. The herbicide glyphosate gave OR = 2.2, 95% CI = 1.3–3.8. Impregnating agents increased the risk. No clear dose-response effect was seen. OR was highest in the >10–20 years latency group for herbicides and impregnating agents. In the multivariate analysis including main pesticide groups, statistically significant increased risk was found for herbicides, OR = 1.6, 95% CI = 1.2–2.1 and impregnating agents with OR = 1.4, 95% CI = 1.1–1.8. This analysis confirmed an association between NHL including HCL and exposure to certain herbicides. [ABSTRACT FROM AUTHOR]

Cladribine is a purine analog used in first-line treatment of hairy cell leukemia and in relapsed/refractory chronic lymphocytic anemia. Although cladribine is typically associated with mild, self-limited skin reactions, there is increasing evidence that cladribine may increase the risk of severe cutaneous adverse reactions (SCAR) when combined with drugs classically associated with SCAR (e.g. allopurinol) beyond what would be expected for either drug alone, possibly due to cladribine-induced lymphopenia. We analyzed all SCAR cases reported for cladribine in Janssen's Global Safety Database and found that 26/35 (74.3%) reported concomitant drugs known to be associated with SCAR, most commonly sulfamethoxazole/trimethoprim (SMX/TMP) and allopurinol. In addition, a review of the WHO VigiBase showed that several drugs, including penicillins, SMX/TMP, and allopurinol had a statistically significant contribution to cladribine-associated SCAR. These results lend further support that cladribine may increase the propensity of these drugs to cause SCARs. [ABSTRACT FROM AUTHOR]

Simultaneous occurrence of hairy cell leukemia (HCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (termed CLL) is very rare. Clinical characteristics, pathology and management of these cases have not been well described. We present six patients with CLL and HCL or HCL variant (HCL-v). Of six patients, three were initially diagnosed with CLL and later developed concurrent HCL. Two patients had concurrent HCL or HCL-v and CLL at initial diagnosis. One had HCL first, followed by concurrent CLL. Polymerase chain reaction analysis demonstrated B-cell clonality in all cases, with two distinct clonal populations in four cases, and three clonal populations in one case. Five patients were treated with a combination of a purine analog such as fludarabine, cladribine, and pentostastin with either rituximab or ibrutinib, while one received dabrefenib and trametinib. All patients achieved a durable response to either CLL or HCL-directed therapy with reduction or ablation of coexisting B-cell clones. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia is an indolent neoplasm involving mature B cells with distinct cytologic and immunophenotypic features. It typically presents in older adults with pancytopenia and splenomegaly. We describe a patient who presented with severe anemia and thrombocytopenia, leukocytosis, and splenomegaly. He had an unusually complicated clinical course including pancytopenia refractory to multiple transfusions, oropharyngeal bleeding requiring intubation for airway protection, subdural hematoma after minor trauma, and sepsis due to Staphylococcus aureus bacteremia. This case highlights the importance of considering hairy cell leukemia in the differential diagnosis of all patients with cytopenia and splenomegaly, as this is a disease that has excellent response to treatment with purine analogs. [ABSTRACT FROM AUTHOR]

The relationship between hematological malignancy and chemotherapy on the prevalence of antibiotic allergy label (AAL) is ill-defined. We performed a multicenter retrospective case-control study comparing AAL rates among cladribine-treated hairy cell leukemia (C-HCL) cases, non-HCL cladribine-treated controls (control-1), and fludarabine-treated controls (control-2). The prevalence of AALs in C-HCL patients was 60%, compared with control-1 (14%, p <.01) and control-2 patients (25%, p <.01). The predominant phenotype was maculopapular exanthem (92%). The drugs implicated in AAL causality in C-HCL patients included beta-lactams (81%), trimethoprim–sulfamethoxazole (58%), and allopurinol (69%). C-HCL patients demonstrate high rates of AAL, potentially due to immune dysregulation, impacting beta-lactam utilization. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is an indolent B-cell malignancy, with long-term responses to purine analogs, but with decreasing efficacy and increasing toxicity with repeated courses. Leukemic cells express CD22, CD20, CD25, tartrate-resistant acid phosphatase (TRAP), annexin 1A (Anxa1), and BRAF V600E mutation. HCLv, lacking CD25, Anxa1, TRAP, and BRAF V600E, is more aggressive and less purine analog-sensitive. A molecularly defined IGHV4-34+ variant is also resistant whether HCL or HCLv immunophenotypically. Traces of HCL cells, termed minimal residual disease (MRD), accompany most with complete remission (CR) and may cause relapse. Rituximab has limited single-agent activity, but frequent CR without MRD when combined with purine analog, albeit with chemotherapy toxicities. The anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox can achieve MRD-negative CR in multiply relapsed HCL without chemotherapy toxicities and was FDA approved in 2018 as Lumoxiti. Investigational oral non-chemotherapy options also include Vemurafenib or Dabrafenib/Trametinib targeting BRAF V600E ± MEK, and Ibrutinib targeting Bruton's tyrosine kinase. [ABSTRACT FROM AUTHOR]

Introduction: Hairy cell leukemia (HCL) is a rare, indolent B-cell neoplasm. The classical variant of the disease is characterized by the BRAF V600E mutation, which is present in virtually all cases. How this mutation leads to the signs and symptoms of the disease is currently not known. Areas covered: This review explores the genetic background of HCL, especially the BRAF V600E driver mutation, but passenger mutations and their effects are also included. The clinical significance of BRAF mutations in other cancer types is discussed, as well as BRAF- induced senescence. An overview of the major forms of treatment of HCL (cytostatic drugs, specific BRAF inhibitors, B cell-specific antibodies) is given. Finally, possible mechanisms of the monocytopenia and hairy morphology so typical of this disease are discussed. Expert opinion: Although being a rare disease, HCL and its pathogenesis can yield important information about BRAF-related cancer metabolism. Many aspects of the disease are still unclear, but with the right resources, this could change. This can lead to a more efficient and specific treatment, thus leading to decreased morbidity. [ABSTRACT FROM AUTHOR]

The article presents case study of a 52-year-old man with splenomegaly and lymphocytosis and was diagnosed with variant hairy cell leukemia (vHCL). It is mentioned that the patient was administered with trametinib for the treatment of IGHV4-34 and MAP2K1-mutation. The article further adds that the patient experienced disease relapse after allogeneic transplantation and developed skin nodules and generalized skin rash.

The article discusses a study on the detection of activating MAP2K1 mutations in patients with atypical hairy cell leukemia and hairy cell leukemia variant (HCLv). The study investigated the cases of patients who also demonstrated the BRAFV600E mutation. The results showed the association of MAP2K1 mutations with preferential usage of the IGHV4-34 variable gene segment.

The majority of patients with hairy cell leukemia (HCL) achieve a response to therapy with cladribine or pentostatin with or without rituximab. However, late relapses can occur. Treatment of relapsed HCL can be difficult due to a poor tolerance to chemotherapy, increased risk of infections and decreased responsiveness to chemotherapy. The identification ofBRAFV600E mutations and the role of aberrantMEKkinase and Bruton's tyrosine kinase (BTK) pathways in the pathogenesis of HCL have helped to develop novel targeted therapies for these patients. Currently, the most promising therapeutic strategies for relapsed or refractory HCL include recombinant immunoconjugates targeting CD22 (e.g. moxetumomab pasudotox),BRAFinhibitors such as vemurafenib and B cell receptor signaling kinase inhibitors such as ibrutinib. Furthermore, the VH4-34 molecular variant of classic HCL has been identified to be less responsive to chemotherapy. Herein, we review the results of the ongoing clinical trials and potential future therapies for relapsed/refractory HCL. [ABSTRACT FROM PUBLISHER]

Background: For a number of decades, hairy cell leukemia (HCL) has been linked with polyarthritis, vasculitis, Symptomatic cytopenias and thrombosis in the medical literature. Notwithstanding, the significance of these associations has not been well understood. Therefore, we have decided to analyze them further. Methods: We provide herein a comprehensive literature review of the prevalence of autoimmune disorders in patients with HCL. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to February 2014. Findings: Perhaps due to the rarity of HCL, scientific literature on autoimmune conditions in patients with HCL consists mainly of published case series and isolated reports. Our analysis identified increased prevalence of various autoimmune conditions in patients with HCL, including various vasculitides, immune cytopenias and antiphospholipid antibody syndrome (APS) among others. Conclusions: Presence of certain autoimmune disorders should increase the suspicion of HCL in an appropriate clinicolaboratory context. Conversely, the diagnosis of HCL should prompt early recognition of certain autoimmune disorders if clinical suspicion exists. While some of these autoimmune diseases are thought to be secondary to the dysfunctional immune response associated with underlying malignant process, others could be primary and might even play a role in the HCL pathogenesis. The autoimmune complications can pose important clinical problems for the HCL patients. Therefore, a catalogue of these problems is important for alerting physicians to watch for them and diagnose them promptly. [ABSTRACT FROM AUTHOR]

Purine analogs are highly effective in hairy cell leukemia (HCL) with response rates of 85%, but with many late relapses. We have retrospectively reviewed the clinical data from 107 patients treated with pentostatin ( n = 27) or cladribine ( n = 80), to investigate the long-term efficacy and to identify factors associated with the treatment-free interval (TFI). Complete remission and minimal residual disease (MRD) rates were similar in both groups. Median TFI was shorter (95 vs. 144 months) in the pentostatin group, although the difference was not significant ( p = 0.476). MRD+ patients had shorter TFI than MRD− patients (97 months vs. not reached, p < 0.049). A hemoglobin level < 10 g/dL predicted for a shorter TFI only in the pentostatin group. Quality of response and number of hairy cells in the bone marrow are independent risk factors of treatment failure. The relationship between MRD+ and shorter TFI makes it of special interest to explore consolidation therapy with monoclonal antibodies to achieve durable responses. [ABSTRACT FROM AUTHOR]

Treatment of hairy cell leukemia (HCL) with cladribine induces durable remissions. Common toxicities are myelosuppression and immunosuppression with low counts of CD4 + T cells. Skin rash (SR) is seldom described. We collected clinical and laboratory data of 35 patients with HCL treated in Hadassah between January 1999 and February 2010, in order to evaluate the frequency and characteristics of SR after treatment with cladribine. We found a high frequency of SR in our group of patients (18/35 patients, 51%), mostly related to febrile neutropenia and concomitant treatment with penicillins/trimethoprim-sulfamethoxazole (TMP-SMZ). The lymphocyte count was low in all patients with SR. We conclude that patients with HCL treated with cladribine have an increased rate of drug hypersensitivity, possibly due to T-cell imbalance induced by cladribine. Since TMP-SMZ and penicillins are related to SR in most cases and are important in the management of patients with HCL, a desensitization protocol should be considered. Rechallenge may be safe after immune reconstitution. [ABSTRACT FROM AUTHOR]

Twenty-nine consecutive patients with hairy cell leukemia (HCL) were treated in two institutions with interferon (IFN, n = 18) or cladribine (n = 11), between July 1987 and May 2011. Median age was 62 (range 29-83) years; there were 21 males and 8 females. Seven of the 18 patients in the IFN group (39%) achieved a complete remission (CR), whereas all the patients in the 2-CDA group entered a CR. Three patients in the 2-CDA group relapsed and needed an additional course of the drug, 2, 3 and 6 years after the initial one. The median overall survival (OS) of the whole group has not been reached, being above 217 months, the 217-month OS being 91%. The survival of patients treated with either IFN or 2-CDA was not statistically different (94% OS at 217 months versus 91% OS at 133 months, respectively). The data that we present here suggest that treatment of HCL with either 2-CDA or IFN is equally effective; treatment costs with IFN are substantially lower than those of the purine analog. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the morphology, immunophenotype, and splenic histology of hairy cell leukemia (HCL) in a 54-year-old male who exhibited an aggressive clinical course.

Over the past 25 years we have collected data at our institution from 242 patients with hairy cell leukemia (HCL), treated with pentostatin ( n == 188) or cladribine ( n == 54), with a median follow-up of 16 years. From this we have been able to conclude that there is no significant difference in outcome between the two agents either at first or subsequent lines of therapy. Overall, the complete response (CR) rate is 81%% and the median disease-free survival (DFS) is 16 years. After relapse or non-response patients can be successfully retreated with pentostatin or cladribine achieving a lower rate of CRs with each line of therapy, although these remain equally durable. Complete response and pretreatment counts of hemoglobin >10 g/dL together with platelets >100 ×× 109/L are associated with the longest DFS. Importantly, for patients achieving a CR the DFS is five times as long as for those achieving a partial response (PR). Patients still in CR at 5 years have only a 25%% risk of relapse by 15 years. Outcomes for patients with recurrent disease have improved with the addition of rituximab to either purine analog. Overall, only eight patients have died of HCL-related causes. Patients with HCL who achieve a CR can expect a normal lifespan. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is an indolent, mature B-cell lymphoproliferative malignancy that clinically manifests as pancytopenia and fibrosis of the bone marrow, ultimately leading to recurrent infections and splenomegaly. This article reviews the extensive experience at Scripps Clinic with cladribine (2-chlorodeoxyadenosine; 2-CdA) in HCL. It is currently recommended as first-line treatment in HCL, because of its proven efficacy with associated low toxicity profile and brevity of treatment duration, with the majority of responses being complete (CRs). This was achieved after only a single 7-day infusion. We also discuss the success of cladribine in patients with relapsed and refractory HCL and potential approaches to eradicating minimal residual disease (MRD). MRD is thought to predict for future relapses. The eradication of MRD warrants continued study in order to further improve disease-free survival, which may translate into ultimately curing patients with HCL. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is a disease with distinctive clinical findings, as well as a unique morphology and immunophenotype. These features typically allow for a reliable and reproducible diagnosis in nearly all situations. However, certain morphological features of HCL, such as villous cytoplasmic projections or characteristic tissue specific infiltrative patterns, including red pulp expansion with pseudosinuses, may be seen in other B-cell lymphoproliferative disorders. A methodical and thorough approach evaluating the clinical, cytological, histological, architectural, and immunophenotypic features is described and will aid in rendering the appropriate diagnosis. This is paramount as current data indicate that hairy cell leukemia -- variant and other splenic B-cell lymphomas must be distinguished from HCL, as the response to therapy differs in these disorders. [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]

The introduction of cladribine and pentostatin for the treatment of hairy cell leukemia (HCL) has dramatically altered the natural history of the disease, and a single course of cladribine given as a subcutaneous injection for 7 days induces complete remission in the majority of patients. A systematic evaluation of the immediate and long-term side effects induced by purine analogs reveals that most of the available information relates to fludarabine, and mostly refers to the use of this agent in the treatment of indolent lymphoproliferative disorders (LPDs) and and chronic lymphocytic leukemia (CLL). Surprisingly, although purine analogs have been used for more than 30 years in the treatment of HCL, there are still not many reports on the toxicity of pentostatin and cladribine other than the early therapy-induced toxicity encountered in the initial management of patients. Only a few studies have evaluated the long-term adverse effects of purine analogs on the immune system or stem cell toxicity, and most of these are not very recent. In addition, the issue of the prevalence of secondary malignancy linked with the therapy of HCL still remains controversial. In this review the available data on cladribine and pentostatin toxicity in the treatment of HCL are summarized, emphasizing immune suppression, stem cell toxicity, and possible correlation with the development of second malignancy. Other rare toxicities are also described, and the special conditions that need to be taken into account when starting treatment for patients with HCL are also considered. [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 is often reported as a disease of young males. The male predominance is strong, 4:1, but the median age in the Swedish national compulsory cancer registry is similar to that of follicular lymphoma, i.e. 62 years. The overall 6-year survival in the Swedish registry of patients diagnosed since 2000 is 80%%, 93%% of patients <60 years, and 68%% of those >60 years. The yearly risk of secondary cancers is 1.75%%. Cladribine is a prodrug which is selectively activated intracellularly. The intracellular initial half-life is 13 h and the terminal half-life is 30 h. Subcutaneous injection once daily is simple and effective due to 100%% bioavailability and no local side effects from injection, and self-administration is easy. Long-term follow-up of Scandinavian patients treated with cladribine (mostly as subcutaneous injections) in the early 1990s shows a >80%% 15-year survival from cladribine treatment in <60 years of age, but <50%% in older patients. Survival from diagnosis of these patients was similar for those previously treated and untreated. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia variant (HCLv), described 30 years ago, was reported to present with high disease burden and less often leukopenia, and later was reported to be resistant to purine analogs. Patients with HCLv were overrepresented among patients with HCL seeking relapsed/refractory trials. To compare clinical and molecular features of classic HCL (HCLc) and HCLv, 85 rearrangements expressing immunoglobulin variable heavy chain were sequenced, taken from 20 patients with HCLv and 62 with HCLc. The gene VH4-34, commonly used in autoimmune disorders, was found in eight patients (40%%) with HCLv versus six (10%%) with HCLc ( p == 0.004). Ninety-three percent of the VH4-34 rearrangements were unmutated, defined as >98%% homologous to the germline sequence. Clinical features of VH4-34++ patients that were similar to those with HCLv included higher white blood cell counts at diagnosis ( p == 0.002) and lower response ( p == 0.00001) and progression-free survival ( p == 0.007) after first-line cladribine, and shorter overall survival from diagnosis ( p < 0.0001). It was found that VH4-34 was independent from HCLv and a stronger predictor than HCLv in associating with poor prognosis. We conclude that VH4-34++ hairy cell leukemia, which only partly overlaps with HCLv, is associated with poor prognosis after single-agent cladribine. However, cases are observed which respond well to antibody therapy either alone or in combination with purine analog. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is a highly treatable, but generally incurable B-cell lymphoproliferative disorder with a long natural history. The purine analogs cladribine and pentostatin are the treatments of choice and both induce complete remission (CR) by peripheral blood counts and morphologic examination of the marrow in the large majority of patients. However, some patients, otherwise in apparent CR, have evidence of minimal residual disease (MRD) as detected by a number of different techniques, including immunohistochemistry, immunophenotypying by flow cytometry, and polymerase chain reaction (PCR). Immunohistochemistry is readily available, but precise criteria which constitute MRD are not uniform. Immunophenotyping can identify a characteristic immunophenotype, but leukemia cells may be difficult to obtain from a fibrotic bone marrow. Patient-specific PCR, while highly specific, is not readily available. Furthermore, the introduction of newer effective therapies such as the monoclonal antibody rituximab and immunoconjugate BL22 following a purine analog or concurrently with a purine analog may eradicate MRD. However, the optimal method for detecting MRD is not known. Furthermore, whether the eradication of MRD improves overall survival has not been established. [ABSTRACT FROM AUTHOR]

The purine analogs pentostatin and cladribine are effective treatments for hairy cell leukemia (HCL). However, alternative treatments are needed for patients with recurrent disease. We reviewed retrospectively data from 18 patients who were retreated with either pentostatin ( n == 12) or cladribine ( n == 6) in combination with rituximab, after 1--6 (median 2) previous treatments with either purine analog as a single agent. All 18 patients responded to therapy, with a complete response (CR) rate of 89%%. This compared favorably with CR rates of 68%% after second-line therapy and 47%% after third-line therapy in 88 patients retreated one or more times with a purine analog alone. Toxicity with the combination treatment was minimal. At a median follow-up of 36 months (range 5--83 months) all 16 complete responders remained in CR, while one partial responder developed recurrent disease at 10 months. The estimated recurrence rate at 3 years was 7%%. This compares with 21%% after second-line therapy and 42%% after third-line therapy in the 88 patients retreated with a purine analog alone. Furthermore, it was a marked improvement on the 55%% recurrence at 3 years previously seen in these same 18 patients after their own first-line treatment with single-agent pentostatin or cladribine ( p == 0.006). The combination of a purine analog with rituximab was safe and effective for patients with recurrent HCL. The results suggest an added benefit compared with single-agent purine analog therapy. [ABSTRACT FROM AUTHOR]

The B cell receptor (BCR) is the functional distinguishing unit that defines any B cell. Immunoglobulin gene (IG) status is preserved in the neoplastic B cell clone and can provide an indicator of the maturation stage reached by the B cell prior to transformation. In hairy cell leukemia (HCL), several data from IG analysis provide clear hints regarding the cell of origin and the ongoing selective interactions of the tumor BCR with environmental stimuli: HCLs (i) have variable levels of IG somatic mutations, (ii) continue somatic mutations at low levels, (iii) have active processes of IG class switching after transformation, and (iv) have a relatively high frequency of selective events in the light chain of the BCR. It has recently emerged that an unmutated status of the HCL-derived IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome, and aggressive disease. These observations suggest that IG gene analysis may have biological and prognostic relevance in HCL and merits further characterization. [ABSTRACT FROM AUTHOR]

Nucleoside derivative cladribine treatment in hairy cell leukemia (HCL) is a rare example of treatment success in cancer. In fact, HCL is generally responsive to single-agent cladribine and only a minority of patients are refractory. Cladribine was originally administered intravenously as a continuous infusion at a dose of 0.1 mg/kg/day for 7 consecutive days. Subsequently cladribine has been administered intravenously, as a 2 h infusion for 5 consecutive days or weekly for 7 weeks, or subcutaneously. These regimens are all very effective but often show relevant toxicity. The subcutaneous route is easier to administer and may increase compliance of the patient. We have had the opportunity to investigate the efficacy and toxicity of subcutaneous cladribine given at the dose of 0.1 mg/kg/day for 5 or 7 days as a single course in newly diagnosed HCL requiring treatment, in an ongoing Italian multicenter clinical trial. Overall responses have been no different in the two arms, while a much lower infection rate was observed when cladribine was given at the lowest dose. Subcutaneous administration may be deemed a very convenient route since it does not require hospitalization. A reduced dosage of cladribine may also be advantageous since it may be associated with reduced toxicity and may set the dose needed for combinations with antibody treatments. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) was once considered an untreatable form of chronic lymphoid malignancy. Based upon the recognition of the importance of adenosine deaminase to the normal B cell survival and proliferation, a hypothesis was developed that temporary inhibition of this enzyme might be therapeutically successful in treating chronic B cell leukemias. Pentostatin was initially explored in patients with refractory chronic lymphocytic leukemia (CLL). Both pentostatin and cladribine, purine nucleoside analogs, have been utilized to successfully treat HCL. The high degree of complete and durable remission observed with either agent resulted in many believing that the treatment of this rare disease had been fully optimized. However, a considerable number of patients will relapse. While tremendous progress has been made in initial management, the issues related to optimal therapy, timing of initiation of treatment, and discovery of novel agents that may be effective in those who have relapsed are important. Investigational agents currently being explored in chronic lymphocytic leukemia may also have benefit for those patients who have relapsed or are resistant to therapy of hairy cell leukemia. Many important questions remain (e.g. importance of minimal residual disease) and will require international collaboration to fully address these unanswered questions. The Hairy Cell Leukemia Consortium was established to address these unanswered questions. [ABSTRACT FROM AUTHOR]

Recombinant immunotoxins, containing an Fv fragment and a bacterial toxin, frequently elicit neutralizing antibodies, nearly always against the toxin. Moxetumomab pasudotox (previously called CAT-8015 or HA22) contains an anti-CD22 Fv fused to PE38, a truncated form of Pseudomonas exotoxin, containing amino acids 253--364 and 381--613. One avenue to reducing immunogenicity is to identify B- and T-cell epitopes and remove them while retaining toxin activity. To determine B-cell epitopes on PE38, 60 monoclonal antibodies against PE38 were tested in a pairwise manner, and seven major epitope groups with 13 subgroups were identified. The locations of many of these epitopes were identified by mutating large surface-exposed residues to alanine. A mutant of moxetumomab pasudotox containing eight epitope-eliminating mutations (HA22-8X) was prepared, and greatly reduced immunogenicity in mice. In parallel, two large sections of PE38 containing lysosomal protease cleavage sites were removed, leaving only amino acids 274--284 and 394--613 of the toxin. The resulting molecule, HA22-LR, retained cytotoxicity toward CD22++ cell lines, killed primary chronic lymphocytic leukemia cells more potently than moxetumomab pasudotox, was much less toxic to mice, and had significantly improved antitumor activity toward murine xenografts. The immunogenicity and activity of recombinant immunotoxins may be optimized by combinations of these approaches. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a case report concerning the effect of bendamustine in a 47-year-old male patient, who was diagnosed with hairy cell leukemia (HCL) in 1998 after presenting with pancytopenia and splenomegaly.

The B cell receptor (BCR) is the functional distinguishing unit that defines any B cell. Immunoglobulin gene (IG) status is preserved in the neoplastic B cell clone and can provide an indicator of the maturation stage reached by the B cell prior to transformation. In hairy cell leukemia (HCL), several pieces of data from IG analysis provide clear hints regarding the cell of origin and the ongoing selective interactions of the tumor BCR with environmental stimuli. HCLs have variable levels of IG somatic mutations, and continue somatic mutations at low levels as well as IG class switching after transformation. More recent data also show the occurrence of selective events in the light chain of the BCR, suggesting a dominant role for IG status in the pathogenesis of HCL. Moreover, it has recently emerged that an unmutated status of the HCL IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome, and aggressive disease. These observations suggest that IG analysis may have biological and prognostic relevance in HCL and merits further characterization. [ABSTRACT FROM AUTHOR]

The present article describes a comparative study of the performances of liposomes and ethosomes as specialized delivery systems for distamycin A (DA) and two of its derivatives. Liposomes and ethosomes were prepared by classical methods, extruded through polycarbonate filters, and characterized in terms of dimensions, morphology, and encapsulation efficiency. It was found that DA was associated with vesicles (either liposomes or ethosomes) by around 16.0%, while both derivatives of DA showed a percentage of association around 80% in the case of liposomes and around 50% in the case of ethosomes. In vitro antiproliferative activity experiments performed on cultured human and mouse leukemic cells demonstrated that vesicles were able to increase the activity of both derivatives of DA. In addition, it was demonstrated that the aging of both liposomes- and ethosomes-associated distamycin suspensions did not heavily influence the vesicle size, while all samples showed a relevant drug leakage with time. Moreover, according to the different physicochemical characteristics of DA and its derivatives (i.e., log P), vesicle-associated DA showed the highest loss of drug with respect to both its derivatives. In conclusion, the enhancement of drug activity expressed by these specialized delivery systems-associated DD could be interesting to obtain an efficient therapeutic effect aimed at reducing or minimizing toxic effects occurring with distamycins administration. [ABSTRACT FROM AUTHOR]

SOX11 is a transcription factor involved in embryonic neurogenesis and tissue remodeling. Its role in lymphopoiesis is still unknown. Recent studies have shown the specific overexpression of SOX11 mRNA and nuclear protein in both cyclin D1-positive and -negative mantle cell lymphoma (MCL). In addition to MCL, SOX11 is strongly expressed in hairy cell leukemia, Burkitt lymphoma, and immature lymphocytic neoplasms. Expression of SOX11 in MCL is not only a new diagnostic marker, but may also carry information related to the clinical and biological behavior. Further study of the biology may reveal common pathways to neoplasia related to SOX11 expression. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 59-year-old white man with multifocal cranial neuropathies. The patient was diagnosed with hairy cell leukemia (HCL) and was treated with vemurafenib after restaging MRI demonstrated persistent diffuse disease following high-dose cytarabine along with systemic rituximab and intrathecal methotrexate. Complete response and resolution of areas of intracranial enhancement with no new areas of enhancement was observed with treatment of vemurafenib.

Enormous progress has been made in the management of patients with hairy cell leukemia (HCL) over the past 50 years since this disease was initially described in 1958. The introduction of the two commonly used purine nucleoside analogs (pentostatin and cladribine, respectively) has independently changed the natural history of this rare malignancy. Both agents are equivalent in terms of response and long-term results. Advances in therapy are being further pursued with inclusion of monoclonal antibodies (e.g. rituximab) and other immunotherapeutic approaches. Patients with this disease now can live a near normal life expectancy, but the disease has not yet been cured. Clinical trials must continue to address the remaining unanswered questions. [ABSTRACT FROM AUTHOR]

Since its first description in 1958, hairy cell leukemia (HCL) had a long period of different unsatisfactory treatments till the early 1980s, when interferon-alfa and subsequently purine analogs (PAs) pentostatin or cladribine, or pentostatin were described to determine durable responses. However, second lines of treatments are very often needed in the life span of patients with HCL and a small minority of patients are refractory and with poor prognosis. These disadvantages have led to test the efficacy of additional compounds, mainly monoclonal antibodies, combined with PAs. The objective of this presentation is to review the current knowledge of combination treatments in HCL. Combination treatments have been used or proposed for different purposes in HCL: to reduce acute toxicity, to improve complete remission (CR) rate, to overcome resistance/refractoriness, to prolong disease-free survival, or to prolong overall survival. The type of patients to be selected for the combinations and the perspectives of combinations of PAs with monoclonal antibodies will also be discussed. [ABSTRACT FROM AUTHOR]

With the use of nucleoside analogs as frontline therapy, the prognosis of hairy cell leukemia (HCL) has improved dramatically. Unfortunately, disease recurrence remains problematic. Eradication of minimal residual disease (MRD) persisting after therapy may further improve outcome. The evolution of available techniques used to assess MRD, and the potential incorporation of novel agents such as monoclonal antibodies (MoAbs) into the treatment armamentarium for HCL mandate that MRD analyses be performed concurrently with routine assessments of disease status. Herein, the available data regarding the prevalence and clinical relevance of MRD after therapy for HCL is reviewed. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder, but is gratifying to treat for both physicians and patients. During the 50 years since its initial description as a clinical entity, hematologists have been fascinated by the bizarre appearance of the malignant cell with its hair-like projections. Therapeutic strategies have evolved from splenectomy to interfere to the purine analogues which have become the treatments of-choice and are very effective. Immunoconjugate Therapy with BLZZ (anti-CDZZ antibody linked to truncated to Pseudomonas exotoxin) represents the newest milestone in the development of effective treatment for hairy cell leukemia. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is an uncommon B-cell malignancy with unknown pathogenesis. In an earlier study, we demonstrated that HCL cells highly express the transcription factor T-box-expressed-in-T-cells (T-bet). T-bet is the master regulator of the T-helper (Th)1 cell response regulating interferon gamma (IFN-γ) production and also plays a central role in the T-cell independent Th1-like B-cell response. Here, we demonstrate by fluorescence activated cell sorting (FACS) analysis that neoplastic cells from the peripheral blood of five patients with HCL showed an enhanced expression of IFN-γ after stimulation. Additionally, a comparison with 55 healthy individuals revealed a significant elevation of IFN-γ in the sera of patients with HCL. Based on our recent findings that a non-neoplastic B-cell subset, the monocytoid B-cells, are T-bet positive and produce IFN-γ, we propose that monocytoid and hairy B-cells have a similar function and that the T-bet-IFN-γ axis is involved in the pathogenesis of HCL. [ABSTRACT FROM AUTHOR]

Daily administration of 2-chlorodeoxyadenosine (Cladribine, CDA) is a standard treatment for hairy cell leukemia, but may cause severe neutropenia and neutropenic fever. This trial compared toxicity and efficacy of weekly versus daily CDA administration. One hundred patients were randomized to receive standard (CDA 0.14 mg/kg/day day 1-5 [Arm A]) or experimental treatment (CDA 0.14 mg/kg/day once weekly for 5 weeks [Arm B]). The primary endpoint was average leukocyte count within 6 weeks from randomization. Secondary endpoints included response rates, other acute hematotoxicity, acute infection rate, hospital admission, remission duration, event-free, and overall survival. There was no significant difference in average leukocyte count. Response rate (complete + partial remission) at week 10 was 78% (95% confidence interval (CI) 64-88%) in Arm A and 68% (95% CI 54-80%) in Arm B (p = 0.13). Best response rates during follow-up were identical (86%) in both arms. No significant difference was found in the rate of grade 3+4 leukocytopenia (94%vs. 84%), grade 3+4 neutropenia (90%vs. 80%), acute infection (44%vs. 40%), hospitalization (38%vs. 34%), and erythrocyte support (22%vs. 30%) within 10 weeks. Overall, these findings indicate that there are no apparent advantages in toxicity and efficacy by giving CDA weekly rather than daily. [ABSTRACT FROM AUTHOR]

Hairy cell Leukemia (HCL) is a chronic lymphoproliferative disorder that was characterized in the late 1950s. HCL is defined, according to the WHO classification, as a mature (peripheral) B-cell neoplasm (1). HCL accounts for between 2-3% of all leukemia cases, with about 600 new cases diagnosed in the U.S. each year (1). HCL occurs more commonly in males, with an overall male to female ratio of approximately 4:1. The median age of onset is 52 years. This disease is seen more commonly in Caucasians and appears to be especially frequent in Ashkenazi Jewish males, with rare occurrence in persons of Asian and African descents (1). Hairy cells are distinct, clonal B cells arrested at a late stage of maturation. They are small B lymphoid cells that possess oval nuclei and abundant cytoplasm with characteristic micro-filamentous (“hairy”) projections. They strongly express CD103, CD22, and CD11c (2). These cells typically infiltrate the bone marrow, the spleen, and to a lesser extent the liver, lymph nodes, and skin. Many patients present with splenomegaly and pancytopenia. Other clinical manifestations include recurrent opportunistic infections and vasculitis. Historically, HCL was considered uniformly fatal (2). However, recent treatment advances, using purine analogues such as Cladribine and Pentostatin, led to a significant improvement in prognosis with achievement of high response rates and durable remissions (2). [ABSTRACT FROM AUTHOR]

Hairy-cell leukemia is characterised by a marked sensitivity of the malignant cells to the cytotoxic effects of therapeutically administered interferon-α. The aim of this study was to assess the role of protein tyrosine phosphatases in the maintenance of hairy-cell (HC) viability and their sensitivity to interferon-α. The selective tyrosine phosphatase inhibitor mpV(pic) killed HCs, but not normal B lymphocytes or chronic lymphotic leukemia (CLL) cells. HCs displayed increased expression of the phosphatases SHP-1 and SHP-2 when compared with normal B lymphocytes. Phosphatase inhibition also enhanced the cytotoxic effect of interferon-α against HCs in four of the five cases tested. Therefore, HCs, but not normal B cells or CLL-cells, require tyrosine phosphatase activity for preservation of their viability. In addition, HC sensitivity to interferon is down-regulated by this activity. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding the toxicity in patients with relapsed hairy cell leukemia who are treated with rituximab.