Search

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]

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]

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]

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]

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]

Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin ( n = 188) or cladribine ( n = 45), to investigate the current long-term outlook. Median follow-up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse-free survival was 16 years. After relapse ( n = 79) or non-response ( n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse-free survival was 11 years. After third-line therapy ( n = 23), 50% achieved CR and median relapse-free survival was 6·5 years. However, CRs were equally durable, whether after first, second or third-line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 × 109/l before treatment had the longest relapse-free survival ( P < 0·0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL-related causes. Patients achieving a CR can expect a normal lifespan. [ABSTRACT FROM AUTHOR]

Hairy cell leukaemia (HCL) is a rare B-cell neoplasm for which the molecular mechanisms are largely unknown. High-density genome-wide DNA profiling was performed with Affymetrix 250K arrays to analyse copy number (CN) changes and loss of heterozygosity (LOH) in 16 cases of HCL. Four of 16 cases (25%) demonstrated gross non-recurrent CN deletions. Within the affected regions, we identified genes involved in bone marrow fibrosis ( FGF12) and response to treatment ( TP53) in individual cases. Large regions (>5 Mb) of LOH without any concomitant DNA CN changes were identified in 5/16 (31%) HCL and were indicative of uniparental disomy UD. The germline origin of UD was demonstrated in one case for which a matched normal sample was available. Overall analysis of LOH showed that identical loci were recurrently targeted in chromosomes 1, 2 and 6. As a whole, however, HCL showed a remarkably stable genome. This finding adds to several other features that are unique to HCL among mature B-cell tumours. [ABSTRACT FROM AUTHOR]

The article presents a study which investigated the role of rituximab in combination with pentostatin or cladribine for the treatment of recurrent/refractory hairy cell leukemia (HCL). The authors reviewed the cases of 8 patients who received pentostatin or cladribine combined concurrently or sequentially with rituximab at second-line therapy and at subsequent lines of therapy. They found that the combination of purine analogs with rituximab was safe and effective for patients with recurrent and/or refractory HCL.

The article focuses on high resolution DNA profiling of hairy cell leukemia (HCL). It mentions that HCL is a kind of B-cell tumor which is characterized by the presence of leukemic hairy cells. It reports on data obtained with a high-resolution single nucleotide polymorphism (SNP) array in gene BRAF V600E-mutated HCL cases. It mentions that genome-wide DNA profiles were obtained from high molecular weight genomic DNA using the Genome-Wide Human SNP Array 6.0 from Affymetrix Inc.

A letter to the editor is presented entitled "Complete molecular remission induced by concomitant Cladribine-Rituximab treatment in a case of multi-resistant Hairy Cell Leukemia," published within the issue.

Hairy cell leukemia (HCL) is a distinct clinicopathologic entity that responds well to purine analogs but is sometimes difficult to differentiate from HCL-like disorders (eg, splenic marginal zone lymphoma and HCL variant). We recently identified the BRAF-V600E mutation as the disease-defining genetic event in HCL. In this study, we describe a new, simple, and inexpensive test for genetics-based diagnosis of HCL in whole-blood samples that detects BRAF-V600E through a sensitive allele-specific PCR qualitative assay followed by agarose-gel electrophoresis. This approach detected BRAF-V600E in all 123 leukemic HCL samples investigated containing as few as 0.1% leukemic cells. BRAF-V600E was detected at different time points during the disease course, even after therapy, pointing to its pivotal role in HCL pathogenesis and maintenance of the leukemic clone. Conversely, 115 non-HCL chronic B-cell neoplasms, including 79 HCL-like disorders, were invariably negative for BRAF-V600E. This molecular assay is a powerful tool for improving the diagnostic accuracy in HCL. [ABSTRACT FROM AUTHOR]

Background: Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. Methods: We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL. Results: Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF–MEK–ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. Conclusions: The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.) [ABSTRACT FROM PUBLISHER]