Partial response in hairy cell leukemia with vemurafenib despite early discontinuation due to agranulocytosis.

Vemurafenib is an oral BRAF kinase inhibitor approved since 2012 for the treatment of patients with unresectable or metastatic melanoma with BRAF mutations. Vemurafenib also demonstrated efficacy for patients with hairy cell leukemia genetically characterized by BRAF mutation. Here, we report the case of a 38-year-old female patient without any previous medical history who experienced agranulocytosis associated with erythrodermia after vemurafenib initiation for the treatment of hairy cell leukemia. Agranulocytosis was confirmed with bone marrow examination. Vemurafenib was considered the most probable drug responsible for this agranulocytosis and was thus stopped. We observed a full neutrophils recovery 10 days after vemurafenib cessation without any haematopoietic growth factors. A bone marrow biopsy performed 1 month after aplasia ending showed a good partial response with less than 5% of hairy cells remaining. To our knowledge, this is the first case ever described by vemurafenib-induced agranulocytosis. Thus, physicians should be warned about this risk given the growing number of patients treated with vemurafenib.

Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial.

In patients with thalassemia intermedia (TI), such as beta-TI, alpha-thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta-thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5-year long-term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P-value = 0.035). The overall period of observation was 235.2 person-years for the deferiprone patients compared with 214.3 person-years for the deferoxamine patients. The results of the log-rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P-value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long-term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated.

[Pulmonary artery catheterization in patients with blood diseases].

PURPOSE OF THE STUDY: To analyze complications of the pulmonary artery catheterization in patients with blood diseases. MATERIALS AND METHODS: 93 cases of pulmonary artery catheterization in patients with blood diseases were included in the retrospective study. RESULTS: Indications for pulmonary artery catheterization were septic shock (78.5%) and acute respiratory failure (21.5%). In 31 cases (33.3%) pulmonary artery catheterization was performed in conditions of agranulocytosis and in 81 cases (87%) in conditions of thrombocytopenia (platelets median 43 x 109 per liter minimal 7 x 109, maximal 150 x 109 per liter). Patients received transfusions of platelets in case of thrombocytopenia less than 30 x 109 per liter. Early complications of pulmonary artery catheterization occurred in 5 patients with thrombocytopenia (5.4%), the complications was connected with bleeding (hematoma, bleeding from place of puncture, lung bleeding) and mechanical (arterial puncture, pneumothorax, hemothorax). Number of attempts of the central vein catheterization was risk factor the complications. The frequency of catheter-associated sepsis was 5.89 cases each 1000 catheter-days and the frequency of infections of the soft tissues was 9.78 cases each 1000 catheter-days. Catheter-associated infection complications occurred in cases of catheter use over 5 days. Catheter-associated sepsis occurred in 2 of 3 patients with agranulocytosis. Other complications included intermittent arrhythmias during catheter moving in the heart chambers (58), catheter balloon rupture (4), and thrombosis of catheter lumen (3). CONCLUSIONS: Pulmonary artery catheterization can be used in patients with blood diseases and first of all in cases of septic shock and acute respiratory failure. Alternative less invasive methods of monitoring should be used in patients with agranulocytosis.

Suppression of the stem cell antigen-1 response and granulocyte lineage expansion by alcohol during septicemia.

OBJECTIVE: Granulocytopenia frequently occurs in alcohol abusers with severe bacterial infection, which strongly correlates with poor clinical outcome. Knowledge of the molecular mechanisms underlying the granulopoietic response to bacterial infection remains limited. This study investigated the involvement of stem cell antigen-1 expression by granulocyte lineage-committed progenitors in the granulopoietic response to septicemia and how alcohol affected this response. DESIGN: : Laboratory investigation. SETTING: University laboratory. SUBJECTS: Male Balb/c mice. INTERVENTIONS: Thirty mins after intraperitoneal injection of alcohol (20% ethanol in saline at 5 g of ethanol/kg) or saline, mice received an intravenous Escherichia coli challenge. MEASUREMENTS AND MAIN RESULTS: E. coli septicemia activated stem cell antigen-1 expression by marrow immature granulocyte differentiation antigen-1 precursors which correlated with an increase in proliferation, granulocyte macrophage colony-forming unit production, and expansion of this granulopoietic precursor cell pool. Acute alcohol treatment suppressed stem cell antigen-1 activation and inhibited the infection-induced increases in proliferation, granulocyte macrophage colony-forming unit production, and expansion the of immature granulocyte differentiation antigen-1 precursor cell population. Consequently, recovery of the marrow mature granulocyte differentiation antigen-1 cell population after E. coli challenge was impaired. Stem cell antigen-1 was induced in sorted granulocyte differentiation antigen-1, stem cell antigen-1' cells by lipopolysaccharide-stimulated C-Jun kinase activation that was also inhibited by alcohol. Furthermore, stem cell antigen-1 knockout mice failed to expand the marrow immature granulocyte differentiation antigen-1 cell pool and demonstrated fewer newly produced granulocytes in the circulation after the E. coli challenge. CONCLUSIONS: Alcohol suppresses the stem cell antigen-1 response in granulocyte lineage-committed precursors and restricts granulocyte production during septicemia, which may serve as a novel mechanism underlying impaired host defense in alcohol abusers.

Studies of neutrophil production and turnover in grey collie dogs with cyclic neutropenia.

12 grey collie dogs had cyclic neutropenia with the neutropenia recurring at 11.8+/-0.1-day intervals. The recovery from neutropenia was accompanied by a single wave of myeloid proliferation, an increase in marrow myeloid-labeling indices, and an increase in serum muramidase levels. After recovery from neutropenia during the period when blood neutrophils (PMN) were normal or increased, marrow myeloid precursors became scarce. The decline in marrow precursors and marrow PMN reserves heralded the recurrence of neutropenia. Neither diisopropyl fluorophosphate (DF(32)P) leukokinetic studies nor the rate of development of neutropenia suggested shortened PMN survival as a mechanism for the neutropenia. These studies indicate that the cyclic neutropenia is due to a regularly recurring failure in PMN production.

Cyclic hematopoiesis: the mechanism of cyclic neutropenia in grey collie dogs.

Two grey collie dogs had regular cyclic fluctuations in the number of all formed elements of the blood. The period lengths for all elements for an individual dog were the same, but the pattern of fluctuation for each element was distinctive. Normal dogs lacked periodic fluctuations.The patterns of day-to-day variation in the normal dogs counts were consistent with a first-order autoregressive process of serial dependence (i.e., each observation of the series depends on the last preceding observation and no others). The grey collie counts showed the same pattern of serial dependence after the component of the over-all variability due to cyclic oscillation was removed. These data suggest that a defect of hematopoietic regulation at the stem cell level leads to periodic interruptions of production of all hematopoietic elements and accounts for the cycles seen in the peripheral blood counts.

Periodic hematopoiesis in human cyclic neutropenia.

Human cyclic neutropenia is characterized by severe depression of blood neutrophil levels approximately every 21 days. To investigate the mechanism of cyclic neutropenia four patients were studied with daily complete blood counts, serial bone marrow examinations, marrow reserve testing, serum muramidase determinations, DF(22)P granulocytokinetic studies, and, in one patient, in vivo [(3)H]TdR labeling. Periodogram analysis of the serial blood counts in the latter patient and visual inspection of multiple cycles in the others revealed periodic fluctuations in the levels of blood neutrophils, monocytes, lymphocytes, reticulocytes, and platelets. Rhythmic changes in the morphologic and radioisotopic studies as well as the marrow reserve tests and muramidase measurements were consonant with a mechanism of periodic failure of marrow production rather than peripheral destruction. Human cyclic neutropenia is analogous to cyclic neutropenia in the grey collie dog and may be viewed as the consequence of cyclic hematopoiesis.

Reversal of hemodialysis granulocytopenia and pulmonary leukostasis: A clinical manifestation of selective down-regulation of granulocyte responses to C5adesarg.

The transient granulocytopenia of hemodialysis results indirectly from plasma complement activation by dialyzer cellophane membranes. The C5a(desarg) so produced can induce reversible granulocyte aggregation in vitro and in vivo, and we hypothesized that the pulmonary leukostasis responsible for the granulocytopenia results from embolization of aggregates formed under the influence of C5a(desarg) produced in the dialyzer. These studies were designed to measure C5a(desarg) generation during dialysis by granulocyte aggregometry and to determine the reason for the transience of the leukostasis. C5a(desarg) generation was equally evident throughout dialysis, persisting well after granulocytopenia had reversed, and dialyzer-induced complement activation was insufficient to produce significant depletion of plasma complement titers. That granulocyte deactivation might be responsible for the transience was suggested by the absence of the usual granulocytopenia in a patient with uniquely high levels of C5a(desarg) in his predialysis plasma. Granulocytes drawn from seven stable uremic patients after granulocytopenia had reversed exhibited a dose-related, selective and irreversible refractoriness to stimulation with C5a(desarg), but their responses to n-formyl-Met-Leu-Phe remained normal. Identical deactivation was produced in normal cells by short- or long-term exposure of C5a(desarg) in vitro. These studies suggest that C5a(desarg) is indeed generated by the dialyzer throughout hemodialysis and that the transience of the leukostasis and granulocytopenia is due to selective down-regulation of cellular responses to C5a(desarg)-a phenomenon that hitherto has been described only in vitro and that may be important in limiting the deleterious effects of adherent granulocytes on the endothelium in patients with intravascular complement activation.

Leukokinetic studies. XIV. Blood neutrophil kinetics in chronic, steady-state neutropenia.

The kinetics of blood neutrophils was investigated by means of the in vitro radioactive diisopropyl fluorophosphate method in 35 patients with a chronic, steady-state neutropenia. There were 17 patients in whom the half disappearance time of neutrophils was normal. In 10 of these patients, the production of neutrophils was low and in 7, production was normal. In 18 patients the half disappearance time of neutrophilic granulocytes was shorter than normal. The production of neutrophilic granulocytes was low in five of these patients, normal in eight patients, and increased in five. An attempt was made to correlate other laboratory measurements with the kinetic picture, but no relationship was found; the marrow neutrophil reserve as measured by endotoxin or cortisol injection; marrow cellularity on aspiration or biopsy; in vitro-labeling index with (3)HTdR; or serum lysozyme concentration proved of no value in identifying the various kinetic groups. The only finding that seemed to correlate with the kinetic picture was the presence or absence of splenomegaly. In 12 of the 18 patients with a short half disappearance time, splenomegaly was present whereas in 15 of 17 patients with a normal half disappearance time, there was no splenomegaly. Of 20 patients with greater than 1000 neutrophils per mm(3), 17 were found to have a normal total-blood neutrophil pool. Thus these patients, with many of their cells marginated, agree to have a "shift neutropenia."Myelocyte to blood transit time and myelocyte generation time, as measured in seven patients by in vivo labeling with diisopropy fluorophosphate, proved to be essentially normal. Thus, it appears that in chronic neutropenia, increased or decreased production of neutrophils is accomplished by increasing or decreasing early precursor input into the system.

[Antithyroid agents related agranulocytosis: Literature review]. / Agranulocytoses aux antithyroïdiens de synthèse : revue de la littérature.

The antithyroid agents (carbimazole, methimazole, thiamazole, propylthiouracil and benzylthiouracile) are the drug class that is associated with a high risk of agranulocytosis. Acute and profound (<0.5×10(9)/L) isolated neutropenia occurring in a subject treated with antithyroid agents should be considered as a drug-induced agranulocytosis, until proven otherwise. The clinical spectrum ranges from discovery of acute severe but asymptomatic neutropenia, to isolated fever, localized infections (especially ear, nose and throat, or pulmonary) or septicemia. With an optimal management (discontinuation of antithyroid agents, antibiotics in the presence of fever or a documented infection, or use of hematopoietic growth factor) the current mortality is close to 2%.

Pregnancy complicated with agranulocytosis.

RATIONALE: Pregnancy is a complicated physiological process. Physiological leukocytosis often takes place and it is primarily related to the increased circulation of neutrophils, especially during the last trimester of pregnancy. Noncongenital agranulocytosis during pregnancy is rare and reported only occasionally, while in most of the cases, the agranulocytosis has already occurred prior to pregnancy or induced by identified factors such as antibiotics, antithyroid agents, or cytotoxic agents. Gestation-induced agranulocytosis has not been reported, so we present a case of gestation-induced agranulocytosis in this article. PATIENTS CONCERN: In this case, we present a Chinese woman (aged 25) in her 38th week of the first gestation who had the complication of agranulocytosis. No abnormality was detected in regular examinations before pregnancy and in the first trimester. Since the last trimester of pregnancy, the patient began to suffer from agranulocytosis and intermittent fever, the maximum being temperature 38.8°C. At admission, the neutrophil granulocytes were 0.17 × 10 L and the bone marrow biopsy showed that agranulocytosis was detected, but the levels of red blood cell and megalokaryocyte were normal. In addition, antinuclear antibodies were detected at a dilution of 1:40, but anti-dsDNA, antiphospholipid antibody, and neutrophil granulocyte antibody were negative. DIAGNOSES: The patient was empirically treated as having pneumonia. INTERVENTIONS: We tried to use granulocyte colony-stimulating factor, γ-globulin, glucocorticoids, antibiotics, and antifungi agents to treat the patient, but her symptoms were not alleviated until the patient had a cesarean section. OUTCOMES: After 24 hours of cesarean section, the temperature and neutrophil granulocyte returned to normal. After a year of follow-up, we found that the patient and the baby were healthy. LESSONS: Agranulocytosis during pregnancy seems to be associated with immunosuppression induced by immunoregulations and termination of pregnancy may be effective for refractory pregnancy complicated with agranulocytosis, but further studies are needed to confirm this.

The safety of dental extractions in patients with hematologic malignancies.

Dental disorders have been recognized as major sources of infection in patients with hematologic malignancies (HM). Management of severe dental infections usually includes dental extractions (DE), but the safety of extractions in patients with HM who are at risk for bleeding, sepsis, and poor wound healing has not been well established. In conjunction with an aggressive program of dental care, 142 DE were performed in 26 patients with acute leukemia, myelodysplastic syndromes, and myeloproliferative disorders. Granulocytopenia (less than 1,000 granulocytes/microL) was present during or within ten days following surgery in 14 patients. In these 14 patients (101 DE), the mean granulocyte count was less than 450/microL, with a median duration of granulocytopenia following surgery of 32 days (range, four to 169 days). Thrombocytopenia (less than 100,000 platelets/microL) occurred during or within two days following surgery in 13 patients (80 DE), with a mean platelet count of 63,500/microL. Transfusions were given for platelet counts less than 50,000/microL. All DE were performed without significant complications. Bleeding was minor to moderate and easily controlled with local measures; no patient required transfusion due to hemorrhage. Average maximum temperature 24 hours after DE was 37.7 degrees C. No episodes of bacteremia were documented within ten days of DE. Minor delay in wound healing was observed in two patients. We conclude that DE can be safely performed in patients with HM in combination with aggressive supportive care.

Nebulization of four commercially available amphotericin B formulations in persistently granulocytopenic rats with invasive pulmonary aspergillosis: evidence for long-term biological activity.

The nebulization of amphotericin B desoxycholate (AMB-DOC), liposomal amphotericin B (L-AMB), amphotericin B lipid complex (ABLC) and amphotericin B colloidal dispersion (ABCD) has been investigated. Particle sizes of generated aerosol droplets were measured. Pulmonary amphotericin B deposition and amphotericin B concentration in blood directly after nebulization and at six weeks after nebulization was measured in healthy rats. The efficacy of nebulized amphotericin B formulations was evaluated in persistently granulocytopenic rats with invasive pulmonary aspergillosis. Treatment was given either after or before fungal inoculation. The endpoint was survival of animals. Aerosol particle sizes, expressed as the values for the mass median diameter were 1.38, 2.43, 0.90 and 2.29 microm for AMB-DOC, L-AMB, ABLC and ABCD, respectively. Amphotericin B concentrations in the lungs directly after nebulization exceeded the minimum inhibitory concentration of Aspergillus fumigatus and amphotericin B was still detected in lungs of rats at six weeks after nebulization. Treatment, started at 16 h after fungal inoculation, resulted in a significantly prolonged survival as compared with sham-treated rats for all four formulations. Prophylactic treatment at one week before fungal inoculation resulted in a significantly prolonged survival for all four formulations. Aerosol treatment given at two weeks before inoculation was effective only for AMB-DOC and L-AMB, whereas treatment given at six weeks resulted in a significantly prolonged survival for L-AMB only. All commercially available amphotericin B preparations could be nebulized efficiently and may be of value in the prophylactic treatment of invasive pulmonary aspergillosis.

Cyclic neutropenia: a clinical review.

Cyclic neutropenia is a benign, hematologic disorder characterized by recurrent episodes of severe neutropenia at 21 day intervals. There are associated cyclical variations in other blood cells. Patients with this disease have malaise, stomatitis, cervical lymphadenopathy and fever during the recurrent neutropenic periods. The exact cause of cyclic neutropenia is unknown. About one third of human cases appear to be inherited in an autosomal dominant pattern. In the other cases, the disease appears to arise spontaneously with symptoms usually beginning in infancy or early childhood. In adult patients, the disease may be acquired and occur in association with a clonal proliferation of large granular lymphocytes. Clinical studies in man and investigations in grey collie dogs, which have a very similar disease, strongly suggest that cyclic neutropenia is due to an abnormality in the regulation of early hematopoietic precursor cells. Therapy for cyclic neutropenia involves local and symptomatic therapy for the recurrent mouth ulcers and pharyngitis, and antibiotics for episodes of sinusitis, pneumonia, peritonitis, or bacteremia. Therapy with glucocorticosteroids, androgens, and plasmapheresis has been efficacious in a few adult patients, but no therapy has been proven to alter the cycling of blood counts in children. Despite their repetitive illnesses, patients with cyclic neutropenia grow and develop normally. With the help of attentive physicians and dentists, their quality of life and life expectancy are good. Current research on hematopoietic growth factors offers promise of new approaches to therapy.

Cyclic hormonogenesis in gray collie dogs: interactions of hematopoietic and endocrine systems.

Cortisol, ACTH, T4, and T3 concentrations were determined in six cyclic hematopoietic (CH) dogs to determine if hormonal cycles were a feature of this hematopoietic disorder. It was determined that there were 12- to 14-day cycles of these hormones in CH dogs. Plasma cortisol and ACTH concentrations peaked 4-8 days after the onset of neutropenia and were concurrent with peak neutrophil counts. The peak ACTH concentration occurred 1-2 days before or concurrent with the cortisol peak concentration. T4 and T3 peak concentrations were opposite the cortisol cycles, and maximal concentrations were seen when cortisol levels were lowest. ACTH, GH-releasing factor and TRH response tests were performed in the CH dogs. No frank deficiencies in hormone production were seen with the ACTH, GH-releasing factor, and TRH responses in CH dogs relative to those in normal dogs. It was concluded that cyclic hormonogenesis is a central feature of CH disease. These findings are the first demonstration of extrahematopoietic system cyclicity in this rare disease and suggest the presence of common regulatory factors in the hematopoietic and endocrine systems.

Cyclic neutropenia and T lymphocyte suppression of granulopoiesis: abrogation of the neutropenic cycles by lithium carbonate.

To investigate the mechanisms of cyclic neutropenia, we studied the capacity of a patient's T lymphocytes (TLp) to interact with monocyte-macrophages from her normal HLA-identical sibling (MOb) in the elaboration of colony-stimulating activity (CSA). TLp obtained at the time of decreasing neutrophil counts, increased CSA elaboration (p less than 0.056) when incubated at a 1:1 ratio with MOb. Increasing the TLp to MOb ratios to 3:1 or 5:1 progressively decreased CSA. Also, lithium carbonate, which ordinarily prevents concanavalin A activation of suppressor TL, failed to do so, suggesting that preactivated suppressor TL were present in the patient while neutrophil levels were falling. In similar experiments performed while neutrophil levels were rising these activated suppressor TL were absent. These data suggest that some patients with cyclic neutropenia may have a cyclic increase in suppressor TL activity. As predicted by our in vitro experiments, lithium carbonate administration did not abrogate the first neutropenic cycle, but it did mitigate subsequent cycles.

Neutrophil migration in vivo and in vitro in healthy neutropenic subjects.

Migration of polymorphonuclear leukocytes (PMN) was studied in six healthy subjects with neutropenia (peripheral blood neutrophil count less than or equal to 1.5 X 10(9)/1). Determined as migration differentials, chemotactic and chemokinetic responsiveness tended to be higher in the neutropenic group. Despite this slight tendency to increased responsiveness in vitro, migration in vivo proceeded more slowly in the neutropenic group than in the control group: at 12 hours the leukocyte counts in the skin chamber media were significantly lower, whereas at 24 hours they were nearly normal. Our results show that PMN migration in healthy neutropenic subjects is different from that in healthy non-neutropenic subjects. These differences should be taken into account in the evaluation of the role of aberrant PMN migration in the development of infectious episodes in a neutropenic patient.

Granulocyte function disorders: aspects of development, genetics and management.

The field of phagocytic disorders has attained major biologic and clinical significance in the past 40 years. The development of exciting new techniques in molecular biology and the cellular physiology of signal transduction have made it possible to identify the genetic defects involved in many of these disorders. Moreover through immunopharmacologic intervention, bone marrow or peripheral or cord blood stem cell transplantation along with the prospect of gene therapy, we have begun attempts to at least partially correct genetic defects in cell development and activation pathways in the entire spectrum of phagocyte disorders. Carrier detection and prenatal diagnosis employing with chain reaction techniques or direct nucleotide sequencing in fetal blood have made these diseases potentially preventable or treatable in utero or shortly after birth.

Methylprednisolone inhibits granulocytopenia induced by infusion of complement-activated serum but not of complement-activated plasma in rabbits.

The effect of methylprednisolone was examined on complement-induced granulocytopenia in vivo following infusion of zymosan-activated autologous plasma or serum into rabbits. Methylprednisolone only inhibited granulocytopenia and thrombocytopenia when zymosan-activated serum or fibrinogen-depleted plasma were infused. It was ineffective at preventing granulocytopenia in animals infused with zymosan-activated plasma. Only zymosan-activated plasma contained fibrin monomers which could directly cause granulocytopenia independently of the generation of C5a. Hence, during complement activation in whole blood in vivo, little or no effect of methylprednisolone should be expected in preventing granulocytopenia.

Drug-induced agranulocytosis: review of possible mechanisms, and prospects for clozapine studies.

Although toxicity and inborn errors of metabolism may also be involved, immunological reactions play an important role in the induction of drug-induced agranulocytosis. Drug-induced antibodies may lead to agranulocytosis by at least three different immunological mechanisms. Immune complexes may selectively adhere to granulocytes or their immature precursor cells, the drug may bind to the granulocytes as carriers of the immunogenic drug and finally the drug may induce antibodies directed to granulocyte-specific structures. The use and the interpretation of in vitro assays to detect drug-dependent antibodies against granulocytes or myeloid precursor cells are discussed. These assays will be used to detect a possible immunological mechanism involved in clozapine-induced agranulocytosis. Further studies will concern the identification of possible genetic risk factors associated with clozapine-induced agranulocytosis.