Vemurafenib and Obinutuzumab as Frontline Therapy for Hairy Cell Leukemia.

BACKGROUND: Hairy cell leukemia (HCL) is characterized by the underlying genetic lesion of BRAFV600E and responsiveness to BRAF inhibitors. We assessed the safety and activity of the BRAF inhibitor vemurafenib combined with obinutuzumab in patients with previously untreated HCL. METHODS: We conducted a single-arm, multicenter clinical study of vemurafenib plus obinutuzumab. Vemurafenib 960 mg twice daily was administered for four cycles, and obinutuzumab was administered in cycles 2 to 4. The primary end point was complete remission (CR). Secondary end points included assessment of safety, minimal residual disease (MRD), and BRAF allele burden according to digital droplet polymerase chain reaction (ddPCR). RESULTS: Thirty patients were enrolled in the study, and 27 patients completed all four cycles of treatments and achieved CR (90%; 95% confidence interval [CI], 73 to 98). Three patients discontinued the study early because of adverse events and were not evaluable for response. Of the 27 patients who achieved CR, 26 patients (96%; 95% CI, 81 to 99) achieved MRD negativity. BRAFV600E allele was undetectable by ddPCR in all 21 evaluable patients. At a median follow-up of 34.9 months (95% CI, 29.6 to 36.9), no patient experienced disease relapse. The most common vemurafenib-related adverse events were rash and arthralgia. Febrile neutropenia occurred in two patients, and blood or platelet transfusions were required in two patients. CONCLUSIONS: Combined time-limited vemurafenib and obinutuzumab achieved CR in more than 90% of patients with previously untreated HCL. In this small study, acquired vemurafenib resistance or dose-limiting toxicity was not observed. Patients were not observed long enough to reveal secondary malignancies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03410875.)

Hairy Cell Leukemia and Ground Water Contamination With Industrial Solvents: a Case Report.

The industrial solvents benzene and trichloroethylene (TCE) are known carcinogens, and these solvents contaminated the drinking water at Marine Corps Base Camp Lejeune from the 1950s to 1980s. Benzene and TCE are linked to the hematopoietic cancers acute myelocytic and lymphocytic leukemia and chronic lymphocytic leukemia. We report the case of a veteran stationed at Marine Corps Base Camp Lejeune during this period who developed hairy cell leukemia (HCL), a rare form of lymphocytic leukemia. We review his presentation, medical history, solvent exposure, and literature on the carcinogenicity of benzene and TCE. This patient represents a possible link of TCE or benzene to HCL. The case also informs clinicians of the updated epidemiology with regards to clinical findings for HCL.

Occupational exposure to pesticides and lymphoid neoplasms among men: results of a French case-control study.

OBJECTIVES: Investigating the relationship between occupational exposure to pesticides and the risk of lymphoid neoplasms (LNs) in men. METHODS: A hospital-based case-control study was conducted in six centres in France between 2000 and 2004. The cases were incident cases with a diagnosis of LN aged 18-75 years. During the same period, controls of the same age and sex as the cases were recruited in the same hospital, mainly in the orthopaedic and rheumatological departments. Exposures to pesticides were evaluated through specific interviews and case-by-case expert reviews. Four hundred and ninety-one cases (244 cases of non-Hodgkin's lymphoma (NHL), 87 of Hodgkin's lymphoma (HL), 104 of lymphoproliferative syndromes (LPSs) and 56 of multiple myeloma (MM) cases) and 456 controls were included in the analyses. The odds ratios (ORs) and 95% CI were estimated using unconditional logistic regressions. RESULTS: Positive associations between HL and occupational exposure to triazole fungicides and urea herbicides were observed (OR = 8.4 (2.2 to 32.4), 10.8 (2.4 to 48.1), respectively). Exposure to insecticides, fungicides and herbicides were linked to a threefold increase in MM risk (OR = 2.8 (1.2 to 6.5), 3.2 (1.4 to 7.2), 2.9 (1.3 to 6.5)). For LPS subtypes, associations restricted to hairy-cell leukaemia (HCL) were evidenced for exposure to organochlorine insecticides, phenoxy herbicides and triazine herbicides (OR = 4.9 (1.1 to 21.2), 4.1 (1.1 to 15.5), 5.1 (1.4 to 19.3)), although based on small numbers. Lastly, despite the increased ORs for organochlorine and organophosphate insecticides, carbamate fungicides and triazine herbicides, no significant associations were evidenced for NHL. CONCLUSIONS: The results, based on case-by-case expert review of occupation-specific questionnaires, support the hypothesis that occupational pesticide exposures may be involved in HL, MM and HCL and do not rule out a role in NHL. The analyses identified specific pesticides that deserve further investigation and the findings were consistent with those of previous studies.

[Cancers and pesticides: current data]. / Cancers et pesticides: données actuelles.

Pesticides are numerous. The occupational exposure to pesticide increases the risk of non-Hodgkin's lymphoma and hairy cells leukaemia. Numerous studies suggest an increasing of incidence of children cancer in connection with parental pesticide exposure. But, most of epidemiological studies are not conclusive but of the difficulty to measure the exposure to pesticides. The future epidemiological studies may include toxicological analysis in order to measure the exposure.

Development of hairy cell leukemia in a patient treated with cytoreductive agents for essential thrombocythemia.

The association of second malignancies in hairy cell leukemia (HCL) is well recognized. Most of these malignancies are either solid tumors or lymphoproliferative disorders rather than myeloproliferative disorders. But these malignancies are usually related to a complication of the drug treatment for HCL. The chronological sequence of HCL occurring after a hematological disorder is very rarely described. This report describes the first case, to our knowledge, of a patient who developed HCL five years after essential thrombocythemia that was treated with oral cytoreductive agents. Pathogenesis of the coexistence of both diseases is discussed.

Exposure to pesticides as risk factor for non-Hodgkin's lymphoma and hairy cell leukemia: pooled analysis of two Swedish case-control studies.

Increased risk for non-Hodgkin's lymphoma (NHL) following exposure to certain pesticides has previously been reported. To further elucidate the importance of phenoxyacetic acids and other pesticides in the etiology of NHL a pooled analysis was performed on two case-control studies, one on NHL and another on hairy cell leukemia (HCL), a rare subtype of NHL. The studies were population based with cases identified from cancer registry and controls from population registry. Data assessment was ascertained by questionnaires supplemented over the telephone by specially trained interviewers. The pooled analysis of NHL and HCL was based on 515 cases and 1141 controls. Increased risks in univariate analysis were found for subjects exposed to herbicides (OR 1.75, CI 95% 1.26-2.42), insecticides (OR 1.43, CI 95% 1.08-1.87), fungicides (OR 3.11, CI 95% 1.56-6.27) and impregnating agents (OR 1.48, CI 95% 1.11-1.96). Among herbicides, significant associations were found for glyphosate (OR 3.04, CI 95% 1.08-8.52) and 4-chloro-2-methyl phenoxyacetic acid (MCPA) (OR 2.62, CI 95% 1.40-4.88). For several categories of pesticides the highest risk was found for exposure during the latest decades before diagnosis. However, in multivariate analyses the only significantly increased risk was for a heterogeneous category of other herbicides than above.

Previous medical history and medications as risk factors for hairy cell leukaemia.

To investigate the possible role of previous medical history and previous medications as risk factors for hairy cell leukaemia (HCL) we performed a population based case-control study on 121 male HCL patients and 484 controls. The data were collected through a self-administered mailed questionnaire. Elevated odds ratios (OR) were found for a history of appendicitis [OR 1.9; 95% confidence interval (CI) 0.9-4.2] and pneumonia (OR 2.9; CI 0.9-9.6). We found a reduced risk for HCL associated with a history of myocardial infarction (OR 0.3; CI 0.4-2.5), hypertension (OR 0.6; CI 0.3-1.2) and thromboembolic disease (OR 0.6; CI 0.1-2.7). Reduced OR was also associated to a history of diabetes mellitus (OR 0.6; CI 0.1-2.9) and a diagnosis of hyperlipidemia (OR 0.8; CI 0.2-3.6). HCL is an indolent disease with a clinical course of many years and it can not be excluded that the disease leads to metabolic changes, resulting in a changed risk for these diagnoses. When the role of previous medications were investigated, increased OR was found for NSAID (OR 3.4; CI 1.1-10.2). Decreased OR was found for the anti-coagulative agent warfarin (OR 0.4; CI 0.1-1.5). A history of a previous malignancy preceeding the diagnosis of HCL as reported to the Swedish Cancer Registry yielded an increased OR of 3.2 (CI 1.2-8.5). All results must be interpreted with caution, as there is a possibility of misclassification. Medications is difficults to remember, particularly several years after consumption. As many comparisons were made, there is always a possibility of correlations occuring by chance.

Occupational exposure to solvents and hairy cell leukaemia.

OBJECTIVES: The role of occupational exposures in hairy cell leukaemia was investigated through a multicentre, hospital based, case-control study. This paper analyses the role of exposure to solvents other than benzene in hairy cell leukaemia. METHODS: The study included 226 male cases and 425 matched controls, exposure to solvents was evaluated by expert case by case review of the detailed data on occupational exposures generated by specific interviews. Also, exposure to solvents was evaluated with an independently constructed job exposure matrix (JEM). RESULTS: No association was found between hairy cell leukaemia and previous employment in a job exposed to solvents (odds ratio (OR) 0.9 95% confidence interval (95% CI) 0.6 to 1.3). ORs for the main occupational tasks exposed to solvents were around 1 and did not increase with the frequency or the duration of the tasks. No specific type of paint or glue was found to be significantly associated with hairy cell leukaemia. No association was found with exposure to solvents, taken as a whole, with either expert assessments or the JEM. No association was found with aromatic, chlorinated, or oxygenated subgroups of solvents. The ORs did not increase with the average intensity of exposure assessed by the experts, with the frequency of use, or with the duration of exposure. Finally, no association was found with non-occupational exposure to solvents. CONCLUSIONS: The study did not show any association between exposure to solvents and hairy cell leukaemia.

Hematologic malignancies developing in Syrian golden hamsters during induction of pancreatic carcinoma.

We report 30 hematologic malignancies arising in 25 of 236 Syrian golden hamsters (SGH) that received combinations of N-nitrobis(2-oxopropyl)amine (BOP) and Streptozotocin (STZ). Lesions developed with morphological similarity to human small lymphocytic (n = 7), diffuse mixed (n = 2), diffuse large cell lymphoma (n = 13), follicular lymphoma (n = 2), anaplastic large cell lymphoma (n = 3), hairy cell leukemia (n = 2), malignant histiocytosis (n = 1) and discordant lymphomas (n = 5). The types and distribution of these lesions are different from epizootic lymphomas in SGH. We also report a higher percentage (12 versus 4.6%) and the earlier appearance (< or = 40 versus 80-112 weeks) compared with aging-associated spontaneous SGH lymphoma. The features of these hematologic malignancies have not been previously reported in epizootic or aging-associated spontaneous lymphomas and therefore suggest a new class of hematologic lesions in SGH. Benign and atypical hyperplasia correlated with STZ administration (r = 0.97, P = 0.03). The malignant lesions correlated with areas of lymphoid hyperplasia (r = 0.78, P= 0.004). Only one of the 21 untreated SGH spontaneously developed a low grade lymphoma. The unusual types, distribution and occurrence of these lesions may suggest a role for these carcinogens in their induction.

Hairy cell leukaemia and occupational exposure to benzene.

OBJECTIVES: The role of occupational exposures in hairy cell leukaemia (HCL) was investigated through a multicentre, hospital based, case-control study. This paper analyses the role of exposure to benzene in HCL. METHODS: A population of 226 male cases of HCL and 425 matched controls were included in the study. Benzene exposure was evaluated by expert review of the detailed data on occupational exposures generated by case-control interviews. RESULTS: No association was found between HCL and employment in a job exposed to benzene (odds ratio (OR) 0.9 (95% confidence interval (95% CI) 0.6-1.3)). The sample included 125 subjects, 34 cases (15%), and 91 controls (21%) who had been exposed to benzene, as individually assessed by the experts, for at least one hour a month during one of their jobs. Benzene exposure was not associated with a risk of HCL (OR 0.8 (0.5-1.2)). No trend towards an increase in OR was detected for increasing exposures, the percentage of work time involving exposure to > 1 ppm, or the duration of exposure. No findings suggested a particular risk period, when the OR associated with the time since first or last exposure, or since the end of exposure, were examined. CONCLUSIONS: In conclusion, with the low exposures prevalent in the sample, the study did not show any association between benzene exposure and HCL.

Farming, pesticide use and hairy-cell leukemia.

OBJECTIVES: This paper analyzes the role of farming and pesticide exposures in the occurrence of hairy-cell leukemia (HCL). METHODS: The study included 226 men with HCL and 425 matched hospital referents. Pesticide exposure was assessed by expert review of detailed interview data on occupational histories and agricultural activities and exposures. RESULTS: Altogether, 77 cases and 116 referents had farmed for at least six months, giving an odds ratio (OR) of 1.5 [95% confidence interval (95% CI) 1.0-2.2]. Forage growing was reported by 20.8% of the cases and 11.1% of the referents and was associated with HCL (OR 2.8, 95% CI 1.6-4.9), even among farmers who had never handled pesticides (OR 3.4, 95% CI 1.0-11.0). A significant association was found between HCL and pesticide use, the overall odds ratios for insecticide, fungicide, and herbicide use ranging from 1.5 to 2.4. Organophosphorus insecticides were the only agrochemicals with a positive association with HCL after other pesticide exposures, smoking, and forage growing were accounted for. A clear-cut negative interaction was found between smoking and exposure to organophosphorus insecticides. A multivariate analysis yielded odds ratio estimates of 2.8 (95% CI 1.4-5.6) for exposure to forage and 7.5 (95% CI 0.9-61.5) for nonsmokers exposed to organophosphorus insecticides. CONCLUSIONS: The present study argues for a role of organophosphorus insecticides in HCL among nonsmoking farmers and shows an unexpected association with forage growing. No evidence of an association with phenoxyacetic acids, triazines, or organochlorine insecticides was found.

Phorbol ester-induced hairy cell features on chronic lymphocytic leukemia cells in vitro.

Leukemic cells from eight patients with chronic lymphocytic leukemia were isolated and cultured in the continuous presence of 12-O-tetradecanoylphorbol 13-acetate (TPA) at a concentration of 1.6 x 10(-9) M for 4-10 days. Aliquots of cells were then analyzed at intervals of 24-72 hr for changes in morphology, acid phosphatase staining (AP), and expression of two hairy cell-associated surface antigens, HCL1 (CD22, Leu 14) and HCL3 (CD11c, Leu M5). All cases studied showed typical B-CLL phenotype, and only a small proportion of cells expressed CD22 and CD11c (mean 7% and 4.9%, respectively). TPA treatment induced the coexpression of CD22 (mean 49%) and CD11c (mean 48%) and tartrate-resistant acid phosphatase in seven of eight cases. Morphologically, cells in TPA cultures expressed hairy cell features that were evident in light and electron microscopic studies. Collectively these changes indicate that TPA can induce hairy cell features on CLL cells in vitro, suggesting the later maturational stage of HCL compared with CLL.

[Practical and disputable aspects of the effect of benzene-containing organic solvents exemplified by the case of hairy cell leukemia]. / Praktyczne i dyskusyjne aspekty dzialania rozpuszczalników organicznych zawierajacych benzen na przykladzie przypadku bialaczki kosmatokomórkowej.

The aim of this paper is to present difficulties in establishing the causal relationship between many years' combined exposure to benzene and other aromatic hydrocarbons and the occurrence of a rare form of leukemia (hairy cell leukemia) in a worker of patients and lacquers factory. Usefulness of experimental and points epidemiologic studies is critically discussed in order to show the consequences of the etiology of combined occupational exposure.

Chronic lymphoid leukaemia and hairy cell leukaemia due to chronic exposure to benzene: report of three cases.

Three cases of chronic leukaemia, two with chronic lymphoid and one with hairy cell leukaemia are reported. These three leukaemic patients belonged to a series of 58 leukaemic patients with chronic exposure to benzene. The low percentage of chronic leukaemias in this series is discussed.

Hairy cell leukaemia occurring during phenytoin (diphenylhydantoin) treatment.

We describe the case of a patient who developed hairy cell leukaemia (leukaemic reticuloendotheliosis) during phenytoin treatment. Hairy cells were identified by fluorescence, phase contrast and electron microscopy; they contained tartrate-resistant acid phosphatase activity, formed rosettes with mouse but not sheep erythrocytes and bore monoclonal surface immunoglobulin. Because of the association of pseudo- and true lymphomas with phenytoin it is possible that this lymphoproliferative disorder arose as a result of the treatment with phenytoin, possibly in conjunction with sulthiame.

[A case of occupational benzene poisoning combined with tricholeukocytic leukemia]. / Un cas mixte d'intoxication benzénique professionnelle et de leucémie à tricholeucocytes.

Case report of occupational intoxication, with moderate anemia and hypogranulocytosis, in the course of which occurs a hairy cell leukemia. Cytological data are significative in photonic and electronic microscopy: microvilli and granulo-lamellar complexes. Discussion of benzen, as toxic factor in etiology of this leukemia.