Absolute Neutropenia Research Articles

Invasive Mould Disease – Predictive Risk Factors in Acute Leukemia Patients Receiving Intensive Chemotherapy and its Impact on Survival

Background: Invasive mould disease (IMD) after chemotherapy in patients with acute leukemia has traditionally caused much morbidity and mortality. Methods: We conducted a retrospective, matched case-control study of IMD in patients with acute leukemia managed in our institution from January 2004 to March 2007 to determine the incidence and clinical outcomes of IMD, including its impact on 1-year survival. Results: During this period, 172 patients with acute leukemia underwent chemotherapy with curative intent. A probable or proven IMD developed in 19 patients (cases), giving an incidence of 11%. Aspergillus was the commonest mould. Cases were more likely than controls to have prolonged neutropenia, fever that did not respond to carbapenems, a bacteremia and a longer length of stay. Three-month survival was 93.3% among both cases and controls, but one-year survival was 46.7% among cases and 93.3% among controls. Having an IMD appears to impart a higher risk of mortality at one year. Conclusion: The incidence of invasive mould disease in acute leukemia patients receiving chemotherapy is 11%. Absolute neutropenia more than 14 days is a risk factor for IMD. Itraconazole prophylaxis did not reduce the likelihood of an IMD and a change should be considered. Having an IMD appeared to predict mortality at 12 months.

Efficacy and safety of lipegfilgrastim compared with pegfilgrastim in patients with breast cancer who are receiving chemotherapy.

e19587 Background: Cancer chemotherapy frequently causes neutropenia, leading to an increased risk of infections and delays in subsequent chemotherapy treatments. Pegfilgrastim is a pegylated recombinant form of granulocyte colony stimulating factor (G-CSF) that extends the half-life and requires less frequent dosing than nonpegylated G-CSF. Lipegfilgrastim is a glycosylated and pegylated G-CSF. The objective of this study was to compare the efficacy and safety of lipegfilgrastim and pegfilgrastim in chemotherapy-naïve patients with breast cancer who are candidates to receive docetaxel/doxorubicin. Methods: In this double-blind, randomized, active-controlled, noninferiority trial, patients with high-risk stage II, III, or IV breast cancer and an absolute neutrophil count ≥1.5x109 cells/L were randomly assigned to lipegfilgrastim 6 mg (n=101) or pegfilgrastim 6 mg (n=101). Study medication was injected subcutaneously on day 2 of the chemotherapy cycle (4 cycles maximum). Primary efficacy endpoint was the duration of severe neutropenia (days with an absolute neutropenia count <0.5x109 cells/L) during cycle 1. Secondary endpoints included the incidence of febrile neutropenia. Efficacy analysis population included patients who were randomized but did not have major protocol violations. Results: Overall, 37%, 46%, and 17% of patients had stage II, III, and IV breast cancer, respectively. The mean duration of severe neutropenia in cycle 1 was 0.7 days in the lipegfilgrastim group and 0.8 days in the pegfilgrastim group (poisson regression least squares mean [95% CI] -0.218 [-0.498 to 0.062]). 56% and 49%, respectively, did not experience severe neutropenia in cycle 1. Three patients experienced febrile neutropenia; all were in the pegfilgrastim group during cycle 1. 28% of patients in the lipegfilgrastim group and 26% in the pegfilgrastim group had adverse events that the investigator considered to be related to study medication. Three and 7 patients, respectively had serious adverse events. Conclusions: The results of this study confirm that the efficacy of lipegfilgrastim is comparable with pegfilgrastim. No unexpected safety events were observed.

Benefits of Reiki Therapy for a Severely Neutropenic Patient with Associated Influences on a True Random Number Generator

Reiki therapy is documented for relief of pain and stress. Energetic healing has been documented to alter biologic markers of illness such as hematocrit. True random number generators are reported to be affected by energy healers and spiritually oriented conscious awareness. The patient was a then 54-year-old severely ill man who had hepatitis C types 1 and 2 and who did not improve with conventional therapy. He also suffered from obesity, the metabolic syndrome, asthma, and hypertension. He was treated with experimental high-dose interferon/riboviron therapy with resultant profound anemia and neutropenia. Energetic healing and Reiki therapy was administered initially to enhance the patient's sense of well-being and to relieve anxiety. Possible effects on the patient's absolute neutrophil count and hematocrit were incidentally noted. Reiki therapy was then initiated at times of profound neutropenia to assess its possible effect on the patient's absolute neutrophil count (ANC). Reiki and other energetic healing sessions were monitored with a true random number generator (RNG). Statistically significant relationships were documented between Reiki therapy, a quieting of the electronically created white noise of the RNG during healing sessions, and improvement in the patient's ANC. The immediate clinical result was that the patient could tolerate the high-dose interferon regimen without missing doses because of absolute neutropenia. The patient was initially a late responder to interferon and had been given a 5% chance of clearing the virus. He remains clear of the virus 1 year after treatment. The association between changes in the RNG, Reiki therapy, and a patient's ANC is the first to the authors' knowledge in the medical literature. Future studies assessing the effects of energetic healing on specific biologic markers of disease are anticipated. Concurrent use of a true RNG may prove to correlate with the effectiveness of energetic therapy.

Early Virological Response with Consensus Interferon and Ribavirin in HCV Genotype 3 Non-Responders and Relapsers to Pegylated Interferon Based Therapy

Purpose: Data regarding effectiveness of consensus interferon (CIFN) among HCV genotype 3 patients who failed to respond to pegylated interferon and ribavirin is scarce. The aim of this study was to assess the efficacy, safety and tolerability of CIFN and ribavirin in these patients. Methods: This ongoing open label investigators' initiated clinical study includes consecutive patients of age ≥ 18 years. All eligible patients who agreed to participate in the study are receiving CIFN 15mcg/day (INFERGEN; Three Rivers Pharmaceuticals, LLC, USA) plus ribavirin 800-1200 mg daily. If the patients have complete early virological response (EVR) at week 12, the dose of CIFN is reduced to 15 mcg thrice a week for a further 36 weeks. However, the patients are considered “non-responder” and treatment discontinued if there is a < 2 log10 reduction in HCV RNA. Patients with partial EVR will continue to receive daily CIFN plus RBV for further 12 weeks. These partial responders who will have undetectable HCV RNA at week 24 will continue to receive CIFN 15 μgm daily + ribavirin for further 24 weeks. Results: Included in this interim analysis are 46 patients; 26 (57%) were nonresponders and 20 (43%) relapsers to previous pegylated interferon and ribavirin therapy. Median age 44 years (range 25-61), males 27 (59%). The median baseline quantitative HCV PCR 424668 IU/ml (range 647-1.9 x 107). Ten patients were clinically cirrhotic Child Class A. Twenty patients underwent a liver biopsy, with majority of patients(n=9) having stage 3 fibrosis. A total of 37 patients have completed 12 weeks of treatment and 9 patients dropped out during the initial 12 weeks. Out of the 37 patients (20 non-responders, 13 relapsers), 33 (89%) achieved a complete EVR and one partial EVR. Normal values of SGPT at the end of 12 weeks were observed in 11 nonresponders and 12 relapsers. Common side effects were fever, anorexia and myalgias (78%). Absolute neutropenia (count <500) was observed in 2 patients who were given G-CSF. Five patients received erythropoetin to raise the hemoglobin. Six patients received SSRIs for mild depressive symptoms. Two patients developed portosystemic encephalopathy and were dropped out of the treatment. Conclusion: Our HCV genotype 3 patients who were non-responders and relapsers to previous treatment with pegylated interferon and ribavirin have shown a good response to Consensus Interferon plus ribavirin as reflected by the achievement of early virological response in the majority of patients. It would also be interesting to observe a sustained virological response in these patients.

Cytopenia, Dysplasia, and Monocytosis: A Precursor To Chronic Myelomonocytic Leukemia or a Distinct Subgroup? Case Reports and Review of Literature

Chronic myelomonocytic leukemia (CMML) consists of disorders with overlapping dysplastic and proliferative features. The diagnosis of CMML requires absolute monocytosis (> 1000/μL) in addition to other criteria outlined by the World Health Organization (WHO) classification.(1) Monocytosis not reaching 1000/μL has been observed in myelodysplastic syndrome (MDS) and presents a diagnostic challenge in classification especially if increases in leukocyte count occurring during disease shifts the monocyte count into the absolute range. We discuss the laboratory and clinical features of 3 patients with myelodysplasia and associated monocytosis. Absolute neutropenia was the dominant feature at presentation, with mild anemia, thrombocytopenia, monocytosis (as a percentage), multilineage dysplasia, and increased myeloblasts, consistent with a diagnosis of refractory anemia with excess blasts (RAEB). Absolute monocytosis fulfilling the diagnostic criteria for CMML developed over 6-8 months, prompting a change in diagnosis. Two of 3 patients had normal cytogenetic examinations. JAK2 V617F mutation was detected after transformation to CMML in 1 of them; in the other, a novel translocation t(5;12)(p13;q24) was observed at the time of progression to acute leukemia. The use of different diagnostic terminologies--MDS, dysplasia with reactive monocytosis, myeloproliferative, and myeloproliferative/myelodysplastic syndromes by different and even the same pathologists at different times created confusion among the clinicians and patients. The disease course in these 3 patients was characterized by better survival and prolonged time to progression to acute leukemia, than predicted based on the original diagnosis of RAEB, suggesting that MDS with monocytosis may represent a subgroup distinct from MDS or CMML.

Characterization of the Hematologic Phenotype of rpS6 Heterozygous Null Mice as a Model of the Erythroid Failure In Diamond-Blackfan Anemia

AbstractAbstract 2033Diamond-Blackfan Anemia (DBA) is a congenital form of pure red cell aplasia characterized by a hypoproliferative, macrocytic anemia, congenital anomalies, and a predisposition to cancer. DBA, along with a growing number of human diseases, is linked to defects in ribosome biogenesis. Mutations in at least 10 ribosomal protein genes of both the 40S and 60S ribosomal subunits have now been identified in over 50% of patients with DBA (Narla A, et al. Blood 2010; 115) resulting in ribosomal protein haploinsufficency and in turn a defect in ribosome biogenesis. It remains, however, unknown how these events culminate in erythroid marrow failure. The study of this pathophysiology has been hindered by a lack of animal models. We became aware of the Rps6-deleted mouse as a potential murine model of DBA (Volarevic S, et al. Science 2000; 288). RPS6 is another 40S ribosomal subunit protein required for ribosomal subunit assembly. Haploinsufficiency of RPS6 causes a phenotype reminiscent of DBA during embryogenesis (Panic L, et al. Mol Cell Biol 2006; 26), however, the erythropoietic phenotype of the conditionally-deleted Rps6 heterozygous mouse was unknown. The purpose of these studies is to fully characterize the erythroid phenotype of this mouse as a model of DBA. We demonstrate that deletion of one Rps6 allele in mice results in a macrocytic anemia and leukopenia (an absolute neutropenia and lymphocytopenia, Table 1). Though this finding is not typical, neutropenia has been described in DBA. Like DBA, the anemia is hypoproliferative (corrected reticulocyte counts were equivalent in rpS6 heterozygous and control mice: 3.3% ± 0.21, n= 3 vs. 3.6 ± 0.33, n=3; two-tailed Student's t-test, p= 0.08, which is an inappropriately low value given the deleted animals' anemia).Table 1Hematologic parameters of Rps6 heterozygous mice. Control mice n= 24, Rps6 heterozygous deleted mice n= 18; mean ± SEM, two-tailed Student's t-test, 5–6 weeks old, 6–7 weeks post deletion. Mice were a gift from George Thomas, University of Cincinnati.rpS6hetscontrolspWBC, k/ul3.7 ± 0.39.0 ± 0.4<4E-14ANC, k/ul0.9 ± 0.12.1 ± 0.1<4E-10ALC, k/ul2.4 ± 0.26.2 ± 0.3<1E-12RBC, m/ul5.6 ± 0.39.3 ± 0.1<3E-12HGB, g/dl9.2 ± 0.413.9 ± 0.2<2E-9HCT, %32.4 ± 1.445.2 ± 0.4<3E-8MCV, fL58.4 ± 0.848.7 ± 0.4<2E-11MCH, pg16.6 ± 0.315.0 ± 0.2<5E-5MCHC, %28.4 ± 0.330.4 ± 0.50.005RDW, %27.3 ± 1.119.1 ± 0.5<9E-7Platelets, k/ul1679.5 ± 81.9900.5 ± 24.8<2E-8Flow cytometric analyses of bone marrow and spleen double-stained for Ter119 and transferrin receptor (CD71) demonstrate impaired early erythroid differentiation, evidenced by a relative expansion in the proerythroblast and basophilic erythroblast populations. Hematopoietic colony assays confirm this early defect. These data suggest that haploinsufficiency of rpS6 impacts both erythropoiesis and granulopoiesis, and since the mice are not thrombocytopenic, the effect appears lineage specific, rather than occurring in a common progenitor cell. Polysome profiles to confirm a defect in ribosome biogenesis are pending. Since heterozygous mice recapitulate the erythroid phenotype of DBA, we treated the mice with standard and potential DBA therapies. Specifically, mice received 2 mg/kg/day of prednisone for 12 weeks. There was no improvement in the hemoglobin or MCV in treated animals. As DBA and 5q- syndrome myelodysplastic syndrome (MDS) share an erythroid phenotype and both result from a haploinsufficiency of a ribosomal protein, we also tested whether the macrocytic anemia in rpS6 heterozygous mice responds to lenalidomide (Revlimid®, gift from Celgene Corporation, San Diego, CA). Mice received 3 mg/kg/day of lenalidomide by oral gavage for 12 weeks. The hemoglobin increased in control mice and markedly increased in rpS6 heterozygous mice after 12 weeks of therapy (13.5 ± 0.4 to 14.9 ± 0.2, p= 0.0 and 7.9 g/dL ± 0.9 to 10.3 ± 0.8, p= 0.01, respectively; mean ± SEM, Student's t-test, paired). Additionally, the MCV decreased with therapy in both groups (49.1 fL ± 1.4 to 41.1 ± 0.2, p=0.005 and 57.4 ± 1.1 to 53.77 ± 1.4, p=0.08). With the caveat that we did not monitor drug levels achieved in vivo, these data suggest that lenalidomide improves hemoglobinization and deserves further study in DBA. Disclosures:No relevant conflicts of interest to declare.

Invasive Mould Infections (IMI) In Acute Leukemia Patients on Chemotherapy - Can We Win the Battle?

AbstractAbstract 4871Aim: To determine risk factors for, and clinical features of, invasive mould infections in patients with acute leukemia on chemotherapy.Methods: A matched case control study where acute leukemia patients on chemotherapy were identified and clinical data pertaining to their disease, clinical course, IMI characteristics and treatment outcomes were evaluated. This was conducted in a tertiary hospital from 1 January 2004 to 31st March 2007.Results: All acute leukemia patients on chemotherapy receive itraconazole prophylaxis. Nineteen cases of invasive mould infections (IMI) were found in the period, giving an incidence of 11.2%, using only patients undergoing curative chemotherapy as denominator. The incidence in patients receiving the first cycle of chemotherapy was 8.9%; in patients receiving subsequent cycles of chemotherapy was 4%. Thirteen cases were proven by EORTC/MSG criteria, 8 of them by histology without positive cultures. There were 3 proven cases of fusariosis, and 1 each of aspergillosis and nodulisporiosis. Cases were more likely than controls to have had an absolute neutropenia for at least 14 days in the chemotherapy episode in which the IMI was diagnosed (p=0.045), to have been bacteremic prior to the diagnosis of IMI (p=0.045), and to have had fever not responding to a carbapenem (p=0.016). They also had a longer length of stay (51.8 vs 27.2 days, p=0.01). The use of itraconazole as anti-fungal prophylaxis was not less common in cases than controls. Common clinical features noted in cases included fever not responding to a carbapenem (84.7%), cough (42.1%), a rise in alkaline phosphatase (36.9%), breathlessness (26.3%), and hemoptysis (21.1%). A pleural effusion was noted on CXR or CT chest in 52.8% of cases, and a characteristic CT thorax in 47.4% of cases. Sixty-eight percent of cases received amphotericin (conventional or lipid preparation) as part of a febrile neutropenia protocol, though only 15.8% received this agent when an IMI was considered. Clinical improvement was attributed to an increase in ANC in 26.3% of cases, and to the introduction of voriconazole in 10.5%. The next cycle of chemotherapy was delayed for 2 – 4 weeks in 15.8% of cases, and for >4 weeks in 31/6% of cases. Three patients (15.8%) died within three months of IMI diagnosis, 47.4% survived >1 year.Conclusions: Anti-fungal prophylaxis with itraconazole did not reduce the likelihood of IMI and this should be changed. Absolute neutropenia is a risk factor for IMI in patients with acute leukemia. Fever not responding to carbapenems and a rise in ALP may be considered as red flags for clinicians to consider the possibility of an IMI and institute prompt treatment. Disclosures:No relevant conflicts of interest to declare.

Is severe visceral leishmaniasis a systemic inflammatory response syndrome? A case control study

The objective of the study is to identify the main risk factors for death by New World visceral leishmaniasis and establish a coherent pathogenic substrate of severe disease based on clinical findings. Seventy-six deceased inpatients and 320 successfully treated inpatients with VL were studied in a case control study. Bacterial infection and bleeding were mutually exclusive events leading to death. Five risk factors were unique for death by bacterial infection (malnutrition, pulmonary rales, severe anemia, severe absolute neutropenia and higher neutrophil count), while another six were unique for death by bleeding (jaundice, severe relative neutropenia, severe thrombocytopenia, liver injury, kidney failure, higher bone marrow parasite load). Bacterial infection, bleeding, severe anemia, diarrhea, dyspnea, edema, jaundice and bone marrow parasite load were the main syndromes of visceral leishmaniasis among successfully treated patients. The data support the idea that bacterial infections are due to immune paralysis. Broad organ and system involvement is plausibly due to the high production of proinflammatory cytokines, whose actions fit well with visceral leishmaniasis. The syndromes and causative mediators are typical of a slowly developing systemic inflammatory response syndrome.

TRATAMENTO HEPATOPROTETOR FAVORECE A RESPOSTA LEUCOCITÁRIA DE RATOS WISTAR INTOXICADOS POR CCl4

A presente investigação teve por objetivo avaliar o efeito hepatoprotetor de tratamentos com o composto deN- Acetil DL- Metionina (5%) + Cloreto de Colina (2%) + Cafeína (1%) + Tiamina Cloridrato (1%) +Nicotinamida (0,5%) + Piridoxina Cloridrato (0,04%), administrado via Intramuscular (IM) nas doses de 0,2;0,6 e 1,0 L/Kg de peso vivo (PV) , através do estudo leucocitário em ratos Wistar, submetidos à intoxicaçãoaguda com CCl4. Fêmeas (N=147) foram distribuídas aleatoriamente em 21 grupos, constituindo seis diferentes tratamentos, sendo avaliados sete animais por grupo em quatro períodos: dois, quatro, seis e oitodias pós-intoxicação induzida pelo CCl4. Verificou-se neste estudo quadros de eosinofilia e monocitose absoluta em animais não tratados e tratados com a dose mínima de 0,2 mL, sendo estes efeitossignificativamente amenizados em animais tratados com 0,6 e 1,0 mLdo composto hepatoprotetor/kg de PV. Os animais intoxicados e não tratados apresentaram um quadro detrombocitopenia, quando comparado a animais intoxicados e tratados. Houve neutropenia e linfocitoseabsoluta em todos os ratos intoxicados com CCl4, não existindo diferença entre os tratamentos. A análise do leucograma demonstrou que o tratamento com o composto hepatoprotetor favoreceu a respostaleucocitária, por atuar beneficamente sobre a população destas células, corroborando a hipótese de que taiseventos amenizem os efeitos deletérios da intoxicação por CCl4 no tecido hepático.

Where have all the neutrophils gone?

An 8-week-old boy presented with a history of fever associated with an ulcerating rash over both hips that had worsened over the preceding 5 days (fig 1). He was the...

Valganciclovir for cytomegalovirus prevention in solid organ transplant patients: an evidence-based reassessment of safety and efficacy.

BackgroundSeveral anti-viral drugs have demonstrated efficacy in preventing Cytomegalovirus (CMV) infections in solid organ transplant (SOT) patients. The recently approved valganciclovir is the most commonly used and most expensive drug for CMV prevention. The safety and efficacy data have been drawn from a single trial. We hypothesized that valganciclovir may not be as safe as nor more effective than other therapies for CMV prevention.MethodsAll experimental and analytical studies that compared valganciclovir with other therapies for prevention of CMV infection after SOT were selected. Based on meta-analytic and multivariate regression methodologies we critically analyzed all available evidence.FindingsNine studies were included (N = 1,831). In trials comparing valganciclovir with ganciclovir, the risk for CMV disease is 0.98 (95% Confidence Interval (95%CI) 0.67 to 1.43; P = 0.92; I2 = 0%). Valganciclovir was significantly associated with the risk of absolute neutropenia (<1,500/mm3) compared with all therapies (Odds Ratio (OR) 3.63 95%CI 1.75 to 7.53; P = 0.001; I2 = 0%); with ganciclovir only (OR 2.88, 95%CI 1.27 to 6.53; P = 0.01; I2 = 0%); or with non-ganciclovir therapies (OR 8.30, 95%CI 1.51 to 45.58; P = 0.01; I2 = 10%). For a neutropenia cut-off of <1,000/mm3, the risk remained elevated (OR 1.97, 95%CI 1.03 to 3.67; P = 0.04; I2 = 0%). For every 24 patients who receive valganciclovir prophylaxis, one more will develop neutropenia compared to other therapies. The risk of late-onset CMV disease with valganciclovir was similar to ganciclovir and higher than those with non-ganciclovir therapies (OR 8.95, 95%CI 1.07 to 74.83; P = 0.04; I2 = 0%]. One more patient will develop late-onset CMV disease for every 25 who receive valganciclovir compared to treatment with non-ganciclovir therapies. The risk of CMV tissue-invasive disease in liver recipients receiving valganciclovir was 4.5 times the risk seen with ganciclovir [95%CI 1.00 to 20.14] (p = 0.04). All results remained consistent across different study designs, valganciclovir doses, and CMV serostatus.ConclusionsValganciclovir shows no superior efficacy and significantly higher risk of absolute neutropenia, CMV late-onset disease, and CMV tissue-invasive disease compared to other standard therapies. Due to the availability of efficacious, safer, and lower cost drugs (high-dose acyclovir, valacyclovir, ganciclovir), our results do not favor the use of valganciclovir as a first-line agent for CMV preemptive or universal prophylaxis in SOT patients.

Copper Deficiency Remains An Underappreciated Cause of Ineffective Hematopoiesis

Copper deficiency has long been recognized as cause of hematopoietic dysfunction, and diagnosis is straightforward if it is pursued. Over a three year period, we diagnosed copper deficiency in seven pts referred to our university-based hematology and BMT outpatient clinics for evaluation and treatment of myelodysplastic syndrome (MDS) or neutropenia/anemia. This represents approximately 3% of new outpatient referrals carrying an ICD-9 code corresponding to MDS or neutropenia. Patient characteristics are shown in Table 1. Three of the seven pts carried a presumptive diagnosis of MDS, and one had received several months of decitabine therapy. Two patients were actually referred for consideration of stem cell transplantation; the others were referred for evaluation of cytopenias. Six of the seven patients had been evaluated by a hematologist prior to referral. Only 3 of 7 pts in our series had recognized risk factors for copper deficiency such as prior gastric bypass or other GI dysfunction; postulated risk factors in the other pts are included in Table1. All pts in our series were anemic and leukopenic, with absolute neutropenia at presentation. In contrast, platelet counts were normal or elevated in all pts, consistent with most previous reports. Five of the seven pts in our series had neuropathy or myelopathy of variable severity. The hematologic abnormalities responded rapidly and completely to oral and/or IV copper replacement in all pts, although neurologic recovery was slow and incomplete.Conclusions: Our experience indicates that copper deficiency is a relatively common cause of neutropenia and anemia, and the consequences of missing the diagnosis may be substantial, including performance of unnecessary transfusion, chemotherapy, and even stem cell transplantation. Normal or elevated platelet counts and concomitant neuropathy or myelopathy are important clues to the diagnosis. Furthermore, copper deficiency must be considered even in pts without obvious GI absorption abnormalities. Serum copper and ceruloplasmin assays should be incorporated into the routine evaluation of most pts with cytopenias and suspected MDS.Age/genderRef. diagnosisRisk factorAssociated symptomsSerum copper (80–155 mcg/dl)Ceruloplasmin (21–53 mg/dl53FMDS–RAEBunknownSevere sensory-motor neuropathy29743FMDS–RAExcess carbonated soda intake?Severe sensory-motor neuropathy2<255FAnemia, neutropeniaGastricbypasssensory-motor neuropathy4345FPossible MDSGastricbypassNone4366FAnemia, neutropeniaExcess tea intake?Bone pain2Link56FAnemia, neutropeniaPartial gastrectomySevere sensory-motor neuropathy2<236FAnemia, neutropeniaTetrathiomolybdate exposure (lubricants)Moderate sensory-motor neuropathy12

The role of neutropenia on outcomes of cancer patients with community-acquired pneumonia

Although the presence of neutropenia may predispose cancer patients to develop community-acquired pneumonia, the role of neutropenia on their outcomes has not been investigated. The purpose of the present study was to compare clinical outcomes of cancer community-acquired pneumonia patients with and without neutropenia. Patients with cancer, identified in the Community-Acquired Pneumonia Organization database, were divided into two groups according to the type of cancer and the presence of neutropenia: patients with solid cancer without neutropenia versus those with functional or absolute neutropenia. Among the 3,106 community-acquired pneumonia patients enrolled, 135 had cancer without neutropenia and 75 had cancer with neutropenia. No significant difference was found between patients with and without neutropenia regarding mean time to clinical stability (5.4+/-2.7 versus 4.9+/-2.7 days, respectively), mean length of hospital stay (9.2+/-7.7 versus 9.9+/-9.6 days) and in-hospital mortality (18 versus 15%, respectively). Using a multiple logistic regression model, neutropenia was not associated with mortality in cancer patients when adjusting for significant covariates (odds ratio 1.30). Lack of neutropenia, during the initial evaluation of a cancer community-acquired pneumonia patient, should not be considered an indicator of better clinical outcome.

Phase II Multicenter Trial To Evaluate the Safety and Efficacy of Low-Toxicity Treosulfan/Fludarabine Conditioning Prior to Allogeneic Haematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia.

BACKGROUND: The toxicity of commonly used myeloablative regimens is the main factor limiting applicability and restricting upper age limit for allogeneic hematopoietic stem cell transplantation (alloHSCT). However, reduced intensity conditioning (RIC) protocols are associated with high risk of relapse. Previous dose-escalation trials revealed high-dose treosulfan-based conditioning an alternative treatment with myeloablative as well as antileukemic potential, accompanied by low non-hematological toxicity. The goal of this multicenter phase II trial was to evaluate safety and efficacy of treosulfan/fludarabine conditioning in AML patients.PATIENTS AND METHODS: Seventy-five patients (median age 45 years, range 19–59) with AML in 1st (80%), 2nd (17%), or 3rd (3%) complete remission were treated with alloHSCT from either matched related (MRD, 40%) or unrelated donors (MUD, 60%). Preparative regimen consisted of treosulfan 14 g/m2/day on days −6 to −4, fludarabine 30 mg/m2/day on days −6 to −2, and in case of MUD-HSCT additionally ATG (Fresenius) 10 mg/kg/day on days −4 to −2. Graft-vs.-host disease (GvHD) prophylaxis consisted of cyclosporine and short-course methotrexate. 25% of the patients had an increased risk of toxicity for standard myeloablative conditioning regimens because of higher age or co-morbidities.RESULTS: All patients engrafted after a period of absolute neutropenia with the median time to ANC >0.5 G/L and PLT >50 G/L of 21 (13–39) days and 19 (11–48) days, respectively. The cumulative incidence of complete donor chimerism was 72% on day +28 and 92% on day +100. Most frequent CTC grade 3 or 4 complications until day 28 after transplantation were febrile neutropenia (28%), infection in neutropenia (16%), and mucositis (5%). None of the patients experienced severe hepatic toxicity, including VOD. After a median follow up of 457 days (98–988), the probabilities of overall (OS) and disease-free survival (DFS) at 2 years equaled 67% resp. 58% (MRD-HSCT) and 58% resp. 45% (MUD-HSCT, p=NS). The 2-year cumulative incidence of relapse was 34% for MRD-HSCT and 37% for MUD-HSCT, whereas non-relapse mortality was 8% and 17%, respectively. Outcome was not significantly influenced by disease status (CR1 vs. ≥CR2) or age.CONCLUSIONS: Conditioning therapy based on treosulfan at a dose of 3x14 g/m2 in combination with fludarabine is very well tolerated, resulting in a low NRM. The regimen demonstrated reliable efficacy in AML patients with confirmed first or subsequent remission. Further randomized studies are warranted to verify advantageous survival results.

Isolation of Aspergillus in critically ill patients: a potential marker of poor outcome

Objective Recent reports have suggested a rising incidence of pulmonary aspergillosis in intensive care unit (ICU) patients. The aim of this study was to determine the clinical significance of isolating Aspergillus from respiratory samples of critically ill patients. Design Retrospective review of medical records. Setting Tertiary medical center that has a large cancer center. Patients All patients admitted to the ICU between January 1998 and August 2004, in whom Aspergillus was isolated from respiratory samples or lung tissue. Intervention None. Results The charts of 104 patients were reviewed. Aspergillus was isolated for a mean of 6.6 days after ICU admission. Thirty-three percent of patients had hematological malignancy, 10% had absolute neutropenia, 14% had bone marrow transplant, 11% had HIV infection, and 22% had chronic obstructive pulmonary disease. Upon admission to ICU, 79%, 43%, and 19% were on antibiotics, corticosteroids, or immunosuppressive therapy, respectively. Ninety percent of patients required mechanical ventilation. The mean Acute Physiologic and Chronic Health Evaluation II score on ICU admission was 20.6, with predicted mortality of 35.5%. However, the actual ICU mortality rate for the cohort was 50%. Twenty-eight percent of patients were diagnosed with probable or definite invasive pulmonary aspergillosis, and 72% had Aspergillus colonization. On univariate analysis, the significant clinical differences between the 2 groups were the presence of neutropenia ( P < .05), immunosuppressants ( P < .05), antibiotics ( P < .05), or bone marrow transplant ( P < .05). The differences in Acute Physiologic and Chronic Health Evaluation II score, the need for mechanical ventilation, ICU length of stay, and ICU mortality were not statistically significant. On multivariate analysis, the following factors were independently associated with invasive diseases, bone marrow transplantation ( P < .01), hematological malignancy ( P = .02), and broad-spectrum antibiotics ( P = .02). Conclusion Isolation of Aspergillus in critically ill patients is a poor prognostic marker and is associated with high mortality irrespective of invasion or colonization. Those who are neutropenic, on immunosuppressive therapy, on broad-spectrum antibiotics, or had bone marrow transplantation are more likely to have invasive pulmonary aspergillosis.

Large‐scale expansion and transplantation of CD34+ hematopoietic cells: in vitro and in vivo confirmation of neutropenia abrogation related to the expansion process without impairment of the long‐term engraftment capacity

Herein are reported the results obtained in all multiple myeloma patients transplanted with peripheral blood hematopoietic progenitor cells submitted to ex vivo expansion. Patients had blood progenitor cell mobilization with cyclophosphamide and filgrastim. CD34+ cells were expanded for 10 days in a medium containing granulocyte-colony-stimulating factor (G-CSF), stem cell factor, and megakaryocyte growth and development factor (MGDF). Twenty-seven patients underwent transplantation with expanded and nonexpanded cells and 7 patients underwent transplantation with expanded cells only. The median fold cell expansion was 29.1. The number of colony-forming unit-granulocyte-macrophage (CFU-GM) and CD34+ cells, and the long-term culture-initiating cell (LTC-IC) activity increased with median fold values of 14.7, 2.75, and 2.25, respectively. Postmyeloablative neutropenia was abrogated in 24 of 27 patients transplanted with expanded cells plus nonexpanded cells. The median duration of severe neutropenia was 0 days and correlated with the number of cells and CFU-GM infused. Survival was similar to that of a historical control group. Our LTC-IC and NOD-SCID mice studies showed that the expanded cells are able of sustaining long-term hematopoiesis. Seven other patients received transplantation with expanded cells alone. Absolute neutropenia was abrogated in 6 patients. The median duration of neutropenia was 0 days. Two patients who received the lower number of total cells or CFU-GM had brief secondary neutropenia, which resolved after G-CSF injections. CD34+ cells expanded ex vivo can abrogate absolute and severe neutropenia after high-dose therapy. The results of the amplification process are strongly related to the delay of hematopoietic recovery.

Preliminary Toxicity Profile of High-Dose Cyclophosphamide for Severe, Refractory Multiple Sclerosis. IND: 65863.

Introduction: The use of potentially lethal doses of chemotherapy for non-malignant illnesses is often met by clinicians and patients with great apprehension. High-dose cyclophosphamide is a non-bone marrow transplant treatment option for those afflicted by severe-refractory autoimmune illnesses mediated by autoreactive lymphocytes. The goal of this therapy is to eradicate offending autoreactive B and T cells but to spare the pleuripotent blood stem cell of any ill effect and obviate the need for stem cell rescue.While cyclophosphamide dosed at 50mg/kg/day for four consecutive days is a standard off-label dosing schedule common in bone marrow transplantation, the FDA required cyclophosphamide, in this setting, to be considered as an investigational new drug (IND). Here we report the toxicity data on our first six patients with severe, refractory multiple scleroses treated with high-dose cyclophosphamide without stem-cell rescue. It is our goal to enroll 25 patients under this IND.Materials and Methods: Patients were diagnosed with MS by established criteria. All had an extended disability status scale (EDSS) score of ≥3.5 after two standard treatment regimens, a left ventricular ejection fraction of ≥ 45% and a serum creatinine ≤3mg/dL. All patients signed an informed consent approved by the Stony Brook University IRB. Patients received 200mg/kg of cyclophosphamide over fours days. Forced diuresis and MESNA were used for hemorrhagic cystitis prophylaxis. Patients received prophylactic acyclovir, fluconazole and Bactrim. Neutropenic fevers received broad-spectrum antimicrobials. Hematocrits were maintained above 25% and platelets were maintained above 10 x 109/L. Starting on day +10, filgrastim (5mcg/kg/day) was used until evidence of neutrophil recovery.Results: Six patients with a median age of 43 (range: 40–48) years, a median EDSS score of six (range: 4–8) and a median duration of disease for 14 (range: 6–18) years participated in this protocol. Patients experienced absolute neutropenia for a median of 8.5 (range: 6–10) days, received a median of 0.7 (range: 0–2) units of PRBCs and a median of 1.5 (range: 0–2) single unit donor platelet infusions.All patients tolerated treatment very well with only expected toxicities. All patients experienced nausea and vomiting with a maximum toxicity grade of 3, controlled with anti-emetics. Stomatitis was common with a maximum toxicity grade of 3. None required parenteral support. Transient, grade 1, liver enzymes elevation was common. Serum chemistries abnormalities were transient and corrected with fluids and electrolyte administration. Given a median follow-up of 125 (range: 40–230) days it is too early to comment on the long-term anti-MS effects; in early follow-up, five patients remain off all immunomodulatory medications and no patient has incurred a major MS exacerbation.Discussion: High-dose cyclophosphamide without stem-cell rescue studied under IND 65863 appears to be well tolerated and safe. All patients experienced full and spontaneous hematopoietic recovery without stem-cell rescue, thereby eliminating the possibility of accidental autoreactive lymphocyte infusion. We have previously reported a median of 9.5 days (range: 6–15) of absolute neutropenia in a conglomerate of other patients with severe refractory autoimmune illnesses treated in a similar fashion.Conclusion: This data suggests that MS patients treated with high-dose cyclophosphamide do not experience a unique toxicity profile. This data was provided to the FDA.

Rituximab, Bevacizumab (Avastin) and CHOP (RA-CHOP) for Patients with Diffuse Large B-Cell Lymphoma (DLBCL).

IntroductionBevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF). Non-Hodgkin's lymphoma (NHL) patients with a high serum VEGF levels have an inferior overall survival compared to patients with low VEGF levels. Rituximab plus CHOP (R-CHOP) prolongs time to treatment failure and survival in patients with DLBCL. But further improvement is needed, particularly with patients with high-intermediate and high risk international index disease. This study was designed to assess the feasibility of the combination of bevacizumab plus R-CHOP (RA-CHOP).MethodBevacizumab was administered at 15 mg/kg IV on day 1 of each cycle over 30–90 minutes. R-CHOP was administered on day 2 of cycle 1 and on day 1 of subsequent cycles. Patients were monitored for cardiac function with echocardiogram and for proteinuria. Serum levels of bevacizumab and rituximab were measured to assess pharmacokinetics. Serum and urine samples were also analyzed for circulating VEGF. Tumor samples were stained for VEGF by immunohistochemistry.ResultsTwelve patients (10 males, and 2 females) with newly-diagnosed DLBCL were enrolled. The median age was 48 years (range 29–63). Three patients had stage II primary mediastinal, 2 stage III, and 7 stage IV disease. ECOG performance status ranged from 0–1. Nine patients had an elevated LDH with a median international index score of 2 (range 0–3). Nine patients had an international index score of 2–3. A total of 80 cycles (range 2–8; median 7) of RA-CHOP was administered. Bevacizumab was held in 5 cycles in 3 patients-due to 1) elevated liver enzymes in the setting of positive hepatitis C serology, 2) transient proteinuria, and 3) DVT associated with central line. The following grade 3 toxicities were observed: 4 febrile neutropenia with infection related to central line, 2 DVT (both central line associated), 1 elevated liver enzymes, and 2 transient hypertension. Grade 4 toxicities included 3 absolute neutropenia with 2 febrile neutropenia, and 1 HSV esophagitis. Two patients are too early to assess response. Best response included CR in 3, PR in 4 (2 with normal PET scans), SD in 1. One patient progressed and another achieved a PR after 4 cycles but further treatment was not given due to severe depression.ConclusionIn this patient population, treatment with RA-CHOP did not result in any grade 3 or 4 proteinuria, heart failure or bleeding. Hypertension was transient and thrombosis was associated with central line placement. Correlative studies and pharmacokinetics are being analyzed and will be available for presentation.

TID compared to BID mycophenolate mofetil (MMF) improves donor chimerism and engraftment rates without increasing postgrafting toxicities after unrelated peripheral blood stem cell (PBSC) transplantation (HCT) with nonmyeloablative conditioning

The safety and efficacy of 10/10 HLA antigen matched PBSC HCT from unrelated donors (URD)s after nonmyeloablative conditioning with fludarabine (3 x 30 mg/m2) and 2 Gy TBI (FLU/2 Gy TBI) followed by cyclosporine (CSP) and MMF (both given BID) for patients with hematologic malignancies ineligible for conventional HCT was previously demonstrated (Maris, Blood Vol 102, #6). Fifty-nine of the 71 pts who received PBSC grafts had sustained engraftment. In that study, the half-life of mycophenolate acid (active metabolite of MMF) was found to be 3 hours. This suggested that TID dosing of MMF could improve postgrafting immunosuppression and thereby increase engraftment rates. Subsequently, a trial of dose escalated MMF (15 mg/kg TID) while holding other HCT parameters constant was performed in 103 pts given PBSC grafts from URDs after FLU/2 Gy TBI, CSP and MMF, 15 mg/kg TID. The results in 69 patients with sufficient followup in this trial were compared to those in the previous 71 pts given MMF BID. Median (med) age of TID MMF pts was 58 (range 17–70) years and that of BID MMF pts was 54 (range 18–70) years. The med follow-up of pts given MMF TID and BID was 9 and 25 months. The med neutrophil nadir was 100/μl vs.740/μl (p = .01), but duration of absolute neutropenia was similar (8.5 vs 9 days, p = .43) for pts who received MMF TID and BID, respectively. There were trends toward less graft rejection at 1 year (7% vs.16%, p = .06) and higher peripheral blood donor CD3+ chimerism at day 28 after HCT (90% vs 75%, p = .09) with TID versus BID MMF. Other outcomes were not statistically different between TID versus BID patient groups: The cumulative probabilities (CP) of acute grades, II, III and IV GVHD were 40%, 11%, and 1% versus 41%, 10% and 3%, respectively. The CP of chronic GVHD requiring therapy were 40% and 44%, respectively. The Kaplan-Meier estimates at 1 year were 60% and 58% for overall survival, and 44% and 44% for progression free survival, respectively. The CP of relapse was 34% and 41%, respectively. The CP of nonrelapse mortality (NRM) at day 100 and at 1 year were 9% vs.11% and 22% vs.16%, respectively. We tentatively conclude that MMF dosing for URD PBSC grafts after FLU/2 Gy TBI can be safely increased from BID to TID without increasing toxicities, NRM, or relapse rates. TID compared to BID dosing of MMF in this setting may result in higher donor day 28 CD3+ chimerism values and sustained engraftment rates, while other outcomes were comparable.

Lymphocyte subsets in healthy adult Kuwaiti Arabs with relative benign ethnic neutropenia

Relative and absolute neutropenia is frequently seen in the healthy adult Kuwaiti Arab population. Fluorescent monoclonal antibody labelling followed by flow cytometry was used to determine the lymphocyte subsets in 48 normal healthy individuals in the Kuwaiti adult population (24 males and 24 females, age 17–59 years) with relative or absolute neutropenia, and this was compared to age-matched controls (64 males and 63 females). The mean haemoglobin levels were 13.6±1.5 and 13.7±1.5 g/dl in the neutropenic and control groups, respectively. White blood cell counts, absolute neutrophil and lymphocyte counts in neutropenic individuals with the corresponding reference range, taken from the control subjects (in parenthesis) were: WBC, 6.7±1.6×10 9/l (4–10.4×10 9/l), neutrophils, 2.7±0.8×10 9/l (1.87–6.63×10 9/l), lymphocytes, 3.3±0.9×10 9/l (1.4–3.62×10 9/l). Absolute values of lymphocytes, CD2+, CD3+, CD19+, CD4+, CD8+, HLADR+ and CD45RA+ cells were significantly higher in the neutropenic group. The range of values with the corresponding reference ranges, in parenthesis, were: CD2+, 1.61–4.30×10 9/l (0.95–2.99×10 9/l), CD3+, 1.37–4.16×10 9/l (0.83–2.71×10 9/l), CD19+, 0.16–1.09×10 9/l (0.05–0.61×10 9/l), CD4+, 0.70–2.89×10 9/l (0.45–1.65×10 9/l), CD8+, 0.57–1.80×10 9/l (0.29–1.17×10 9/l), HLADR+ 0.27–1.74×10 9/l (0.02–0.62×10 9/l), CD45RA, 0.90–4.63×10 9/l (0.34–2.05×10 9/l), respectively. The levels of natural killer cells, CD56+ cells were significantly lower compared to controls while the values of memory T lymphocytes, CD45RO+ were comparable to controls. These results indicate that difference in the leukocyte subpopulations may also be indicative of differences in the lymphocyte subpopulations and that reference ranges for these cell types in healthy neutropenic and non-neutropenic individuals should be established.