Low Absolute Neutrophil Count Research Articles

Hematological parameters during concurrent chemoradiotherapy as potential prognosticators in patients with stage IIB cervical cancer.

We hypothesized that hemoglobin levels, absolute neutrophil count, and absolute lymphocyte count were associated with radiotherapy response and cancer progression and that they might reflect tumor repopulation during concurrent chemoradiotherapy. This study aimed to investigate these hematological parameters as prognosticators of cervical cancer. We analyzed 105 stage IIB cervical cancer patients treated with concurrent chemoradiotherapy, using log-rank tests and multivariate analyses. Hazard ratios were calculated weekly to evaluate changes in hemoglobin, absolute neutrophil count, and absolute lymphocyte count that were associated with disease-specific survival. Patients were categorized into the high hematological risk (patients with low hemoglobin plus high absolute neutrophil count and/or low absolute lymphocyte count) and the low hematological risk (others) groups according to the median cutoff values. During the second week of concurrent chemoradiotherapy, hematological factors were significantly associated with survival. In multivariate analysis, hematological risk was independently associated with disease-specific survival and progression-free survival. The 5-year disease-specific survival and progression-free survival rates in the high hematological risk group were significantly lower compared with those in the low hematological risk group (81.6% vs 92.6%, p = 0.0297; 73.7% vs 89.3%, p = 0.0163, respectively). During the second week of concurrent chemoradiotherapy, the hematological parameters could predict treatment outcome in stage IIB cervical cancer.

Validation of the 2016 Revision to the World Health Organization (WHO) Classification of Myelodysplastic Syndromes with Diploid Karyotype

▪Introduction:The revised 2016 WHO classification of MDS has highlighted the value of morphologic evaluation and mutation analysis of bone marrow (BM)/ peripheral blood (PB) to further refine prognostication. These highlights include: (1) increased emphasis on lineage dysplasia compared with cytopenias; (2) objective enumeration of blast % for reproducibility; (3) accurate quantification of ring sideroblasts (RS); and (4) mutation analysis for SF3B1 in cases showing RS >5% and TP53 in MDS with isolated del(5q). Most of the proposed changes are within the categories of low-grade MDS. In this study, we evaluated 264 cases of MDS with diploid karyotype using the 2016 WHO system.Methods:We selected consecutive cases of MDS with diploid karyotype with BM morphological evidence of dysplasia and reclassified using the 2016 WHO system. Mutation analysis for SF3B1 (exons 14 and 15), SRSF2 (exon 1) and U2AF1 (exons 2 and 6) was performed using Sanger sequencing. Patient data were collected from the medical record. The Kaplan-Meier method was used to estimate OS and time-to-AML transformation. The associations between outcome and clinical and pathological parameters were determined using univariate and multivariate Cox proportional hazards regression models.Results:The study group included 264 MDS patients: 168 (64%) men and 96 (36%) women with a median age of 66.9 years (range, 28.3 - 89.1). The median hemoglobin, absolute neutrophil count (ANC), platelet count, and white blood cell (WBC) count were 10.0 g/dL, 1.9 x 109/L, 114.5 x 109/L, and 3.5 x 109/L, respectively. The median BM blast percentage was 2.5; 74% of the patients had < 5% BM blasts. MDS sub-classification according to the 2008 WHO classification was: RCUD, n=5 (2%); RA, n=9 (3%); RARS, n=16 (6%); RCMD, n=152 (58%); RAEB-1, n=56 (21%); RAEB-2, n=20 (8%), and MDS-U, n=6 (2%). Reclassification using the 2016 WHO classification: MDS with single lineage dysplasia (MDS-SLD, n=14, 5%), MDS with multi-lineage dysplasia (MDS-MLD, n=112, 42%), MDS with RS (including single lineage and multi-lineage dysplasia, MDS-RS, n=56, 21%); MDS-EB1, n=56 (21%), MDS-EB2, n=20 (8%) and MDS-U, n=6 (2%). Grading of fibrosis using reticulin/ trichrome stains showed absent-minimal fibrosis (grades 0-1) in 56/85 (66%) and moderate-severe fibrosis (2-3) in 29/85 (34%) cases. Mutation analysis for splicing factors was performed on 15 cases. Ten cases with 0-5% RS showed 2 cases each with SRSF2 and U2AF1 mutations. No cases had SF3B1 mutation. 5 cases with >5% RS showed SF3B1 mutations in 4 cases and 1 case each with SRSF2 and U2AF1 mutations.Over a median follow-up duration of 22.4 months (range, 0-156.8), 128 (48%) patients died. The median OS was 46.1 months (95% CI: 32.3, 58.4). Patients categorized as MDS-SLD by 2016 WHO had the best OS (156.8 months), followed by MDS-RS (58.7 months), MDS-MLD (46.3 months) and MDS-EB (21.2 months) (p<0.001). Older age, lower hemoglobin, lower ANC, lower platelet count, ≥5% BM blasts, MDS-EB1 and MDS-EB2 by 2016 WHO were significantly associated with worse OS (≤0.044). Accounting for all significant measures, age, hemoglobin, MDS-EB1 and MDS-EB2 remained significantly associated with OS.Sixteen patients transformed to AML; the median time-to-AML transformation was not reached; 5-year AML transformation rate was 88%. Patients with ≥ 5% BM blasts (p=0.056) and older age (p=0.063) tended to have a higher AML transformation rate.Conclusions:Morphological evaluation of BM/PB (for dysplasia, % BM blasts and RS) provides additional prognostic value and continues to be a critical component for evaluation of MDS patients. Molecular studies for splicing factor mutations are ongoing on all samples with >1% RS. [Display omitted] DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Aberrant Precursor B Lymphoid Blast Population in a Patient with Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a rare mixed myelodysplastic/myeloproliferative neoplasm seen in early childhood. JMML in general is a poor prognosis disease, including risk of transformation to acute leukemic blast crisis in approximately 15% of patients. Like adult chronic myeloid leukemia (CML) the blast phase of JMML is typically myeloid, however B cell and T cell transformations have been reported. Interestingly, in CML, a minority of patients will have a small aberrant B-lymphoblast population that does not inevitably herald progression to B-lymphoblastic blast crisis, however this has not been reported in JMML. Here, we report a case of a child with JMML found to have an aberrant population of precursor B lymphoid blasts.An 11-month-old boy presented to our clinic with splenomegaly and complete blood count (CBC) findings of a low platelet count of 69 x103/UL, low absolute neutrophil count of 0.61 X103/UL and elevated monocytes (36.3%), with an absolute monocyte count of 3.2 x 103/UL. Bone marrow aspirate and biopsy were consistent with JMML with no abnormal blast population reported at the time. Karyotyping confirmed the presence of monosomy 7, with concurrent fluorescent in-situ hybridization (FISH) evaluation showing monosomy 7 in 74% of cells examined. Next generation sequencing on the aspirate revealed a KRAS p.G12A activating mutation at an allele frequency of 35%, further validating the diagnosis of JMML. The patient did not have a matched related or unrelated donor available, thus he was followed closely with serial physical exams, blood counts and bone marrow evaluations. His splenomegaly resolved, blood counts remained stable to improved without intervention, but repeat bone marrow 6 months after the diagnosis showed similar frequencies of monosomy 7 and mutant KRAS. With still no suitable donor available, we opted to pursue a trial of hypomethylating agent, 5-azacitidine that has shown promising results in recent reports. A bone marrow evaluation was done prior to starting azacitidine to establish a pre-therapy baseline. Surprisingly, we were halted by detecting a B lymphoid blast population (6%), with characteristic flow findings, including positive CD45 (dim), CD19, CD10, CD20 (partial), CD22 (dim), CD34, HLA-DR, CD52, CD99, CD58 (heterogeneous) and CD38. Additionally, a new partial CDKN2A deletion was detected by FISH in 10% of cells. These findings were concerning for an emerging precursor B-acute lymphoblastic leukemia, possibly driven by the new CDKN2A deletion. However, we flow sorted the aberrant B cell population from the marrow aspirate, which showed the partial CDKN2A deletion in only 1.25% of these cells, unlike monosomy 7, which was seen in 100% of the abnormal B cell population. A retrospective review of the flow data from the marrow 4 months prior revealed the same aberrant B cell population in a similar percentage (5%) that was originally attributed to hematogones with low CD45 expression. The stability of this population over the course of months was inconsistent with an evolving lymphoid blast crisis. We observed the patient closely, and his blood counts and clinical exam remained stable over the following weeks. A repeat bone marrow showed that the abnormal B-cell population had decreased slightly to 2.6% and the partial CDKN2A deletion was now seen in only 0.4% of the examined cells. Thereafter, treatment with azacitidine (5 daily doses-100mg/m2/dose) was initiated with an excellent response after one cycle, with monosomy 7 detected in only 12% of cells and KRAS allelic burden down to 4.3%. Additionally, the aberrant B cell population declined to 0.15% and partial CDKN2A deletion was not detected by FISH.While longer follow up and additional patients will be necessary to reach definitive conclusions, our case suggests that the immunophenotypic detection of a small, stable abnormal B-lymphoblast population in patients with JMML does not necessarily herald impending acute leukemia. DisclosuresNo relevant conflicts of interest to declare.

ABC transporter polymorphisms are associated with irinotecan pharmacokinetics and neutropenia.

Neutropenia is a common dose-limiting toxicity associated with irinotecan treatment. Although UGT1A1 variants have been associated with neutropenia, a fraction of neutropenia risk remains unaccounted for. To identify additional genetic markers contributing to variability in irinotecan pharmacokinetics and neutropenia, a regression analysis was performed in 78 irinotecan-treated patients to analyze comprehensively three hepatic efflux transporter genes (ABCB1, ABCC1 and ABCG2). rs6498588 (ABCC1) and rs12720066 (ABCB1) were associated with increased SN-38 exposure, and rs17501331 (ABCC1) and rs12720066 were associated with lower absolute neutrophil count nadir. rs6498588 and a variant in high linkage disequilibrium are located in transcriptionally active regions or are predicted to alter transcription factor binding sites. While enhancer activity was not evident in vitro for genomic regions containing these single-nucleotide polymorphisms, rs6498588 was significantly associated with ABCC1 expression in human liver. These results suggest that genetic variation in ABCC1 and ABCB1 may contribute to irinotecan-induced neutropenia by altering expression of transporters involved in irinotecan metabolite disposition.

Moving the Boundaries of Granulopoiesis Modelling.

The human blood cell production system usually remains extremely robust, in terms of cell number or function, with little signs of decline in old age.To achieve robustness, circulating blood cells rely on a formidable production machinery, the hematopoietic system, located in the bone marrow. All circulating blood cells---red blood cells, white blood cells and platelets---are renewed on a daily basis.The hematopoietic system produces an estimated 1e12 cells per day. This is a significant fraction of the 3.7e13 cells in an adult.Robustness is partly due to the short time scales at which cell populations are able to return to equilibrium, combined with large cell numbers and renewal rates. White blood cells (WBCs), among which neutrophils are most prevalent, are the body's first line, innate immune system.Upon infection, WBCs are mobilized from the bone marrow, to increase their number in circulation and fight off pathogen within hours.The 26 billion circulating neutrophils in human have a mean residence time of only 11h in the blood.After their release from the bone marrow, they quickly disappear in the peripheral tissues and are destroyed in the spleen, liver and bone marrow. In addition to the high renewal rate of circulating blood cells, a large number of mature neutrophils, ten times or more the circulating number, is kept in a bone marrow reserve, ready for entering circulation.This high renewal rate and mobilization capability, however, come at a cost. The blood system is an easy target for chemotherapeutic drugs, whose main way of acting is by killing proliferating cells.White blood cells and end especially neutrophils, with their fast turnover, are particularly vulnerable to chemotherapy.Chemotherapy can induce neutropenia---a state of low absolute neutrophil count (ANC)---in cancer patients, which puts them at risk of infection.Homeostatic regulation of white blood cells is mainly controlled by the cytokine Granulocye-Colony Stimulating Factor (G-CSF).G-CSF promotes survival of white blood cell precursors and their differentiation into mature cells.The identification of this protein in the 1980's, and the subsequent development of human recombinant forms of G-CSF paved the way to the treatment of chemotherapy-induced neutropenia.G-CSF therapy as also been successful at treating congenital and other forms of neutropenia.Today, G-CSF is used as an adjuvant in several anti-cancer treatment protocols.The aim of the adjuvant therapy is to minimize the length of the neutropenic episodes.However, exogenous G-CSF administration interferes with white blood cell production regulation.What should be a straightforward effect--administer G-CSF to cause the ANC to increase--turns to be more complicated than that.For instance, it was observed that early timing of G-CSF administration could lead to prolonged neutropenic phase.Thus, in order to take advantage of the full potential of G-CSF, a detailed understanding of the physiological interaction between neutrophils and exogenous G-CSF is necessary. In this issue of the Bulletin, Craig and colleagues present a physiological modelof neutrophil production that includes a detailed modelling of the kinetics of G-CSF.

The Effects of GCSF on the Recovery Time and Duration of Hospitalization in Patients with Anti-thyroid Drug-Induced Agranulocytosis in a Tertiary Hospital

Objectives. This study aims to determine if there is a significant difference in the recovery time and duration of hospital stay of patients with anti-thyroid drug-(ATD) induced agranulocytosis with and without granulocyte colony-stimulating factor (GCSF) therapy. It also aims to describe the clinical characteristics of patients who had anti-thyroid drug-induced agranulocytosis. Methodology. This is a retrospective study of hyperthyroid patients on anti-thyroid drugs (ATD) who had an absolute neutrophil count (ANC) of less than 500/μL. Their charts were reviewed for collection of data on age, gender, body mass index (BMI), type and duration of ATD and use of antibiotic and steroid. Recovery time and length of hospital stay were compared between those who received and did not receive GCSF. Results. TWith similar clinical features between the GCSF and non-GCSF groups, the recovery time from agranulocytosis and duration of hospitalization were significantly shorter in the GCSF group, despite lower ANC. Conclusion. GCSF significantly decreased recovery time (4 versus 7 days, p=0.005) and duration of hospital stay (5 versus 7 days, p=0.009) of hyperthyroid patients with anti-thyroid drug-induced agranulocytosis compared to patients not given GCSF.

Neutropenia as an Adverse Event following Vaccination: Results from Randomized Clinical Trials in Healthy Adults and Systematic Review.

BackgroundIn the context of early vaccine trials aimed at evaluating the safety profile of novel vaccines, abnormal haematological values, such as neutropenia, are often reported. It is therefore important to evaluate how these trials should be planned not to miss potentially important safety signals, but also to understand the implications and the clinical relevance.MethodologyWe report and discuss the results from five clinical trials (two with a new Shigella vaccine in the early stage of clinical development and three with licensed vaccines) where the absolute neutrophil counts (ANC) were evaluated before and after vaccination. Additionally, we have performed a systematic review of the literature on cases of neutropenia reported during vaccine trials to discuss our results in a more general context.Principal FindingsBoth in our clinical trials and in the literature review, several cases of neutropenia have been reported, in the first two weeks after vaccination. However, neutropenia was generally transient and had a benign clinical outcome, after vaccination with either multiple novel candidates or well-known licensed vaccines. Additionally, the vaccine recipients with neutropenia frequently had lower baseline ANC than non-neutropenic vaccinees. In many instances neutropenia occurred in subjects of African descent, known to have lower ANC compared to western populations.ConclusionsIt is important to include ANC and other haematological tests in early vaccine trials to identify potential safety signals. Post-vaccination neutropenia is not uncommon, generally transient and clinically benign, but many vaccine trials do not have a sampling schedule that allows its detection. Given ethnic variability in the level of circulating neutrophils, normal ranges taking into account ethnicity should be used for determination of trial inclusion/exclusion criteria and classification of neutropenia related adverse events.Trial registrationClinicalTrials.gov NCT02017899, NCT02034500, NCT01771367, NCT01765413, NCT02523287

Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project.

Neutrophils are a key component of innate immunity. Individuals with low neutrophil count are susceptible to frequent infections. Linkage and association between congenital neutropenia and a single rare missense variant in TCIRG1 have been reported in a single family. Here, we report on nine rare missense variants at evolutionarily conserved sites in TCIRG1 that are associated with lower absolute neutrophil count (ANC; p = 0.005) in 1,058 participants from three cohorts: Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), and Jackson Heart Study (JHS) of the NHLBI Grand Opportunity Exome Sequencing Project (GO ESP). These results validate the effects of TCIRG1 coding variation on ANC and suggest that this gene may be associated with a spectrum of mild to severe effects on ANC.

Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab

Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need. Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out. The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P < 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR. Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials.

Abstract P4-13-03: Updated safety from a double-blind phase 3 trial (PALOMA-3) of fulvestrant with placebo or with palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy

Abstract Background: Endocrine therapy (ET) resistance remains a major clinical problem for patients (pts) with hormone receptor (HR+) breast cancer (BC). In PALOMA-3, palbociclib (P) combined with fulvestrant (F) demonstrated significant prolongation of progression-free survival (PFS) vs F plus placebo (PLB) in pre/peri and postmenopausal women with HR+/HER2– metastatic BC (MBC) whose disease progressed on prior ET (median PFS 9.2 vs 3.8 m; HR=0.422, P=0.0001). Methods: In this double-blind phase 3 study, 521 pts with HR+/HER2– MBC were randomized 2:1 to receive P (125 mg/d orally for 3 weeks followed by 1 week off) and F (500 mg given per standard of care) or PLB plus F. Pre- and perimenopausal women also received goserelin. One previous line of chemotherapy (CT) for MBC was allowed. Safety assessments occurred at baseline and D1 of each cycle; blood counts occurred every 2 wks for the first 2 cycles and on D1 of subsequent cycles. As pts may have experienced multiple episodes of neutropenia during treatment, we analyzed all episodes in aggregate based on laboratory data per CTCAE4.0. Results: The results reported here are from the data cutoff of Dec 2014, with a median follow-up of 5.6 m. Overall rate of any grade (G) and G3/4 AEs was 98/70% of pts in P+F vs 89/18% in PLB+F. The most commonly reported AEs in P+F (≥20%) were hematologic toxicities, fatigue, nausea, and headache. Per lab data, G3/G4 neutropenia occurred in 52.2/8.2%, G3/G4 leukopenia in 39.5/1.2%, G3/G4 anemia in 20.8/2.9% and G3/G4 thrombocytopenia in 2.1/1.2% of pts on P+F. Neutropenia occurred early, with a median onset time for first episode of ≥G3 neutropenia of 15 d (13–197) and median time from first dose to the lowest absolute neutrophil count (ANC) of 29 d (13–334). The median duration of ≥G3 episode was 7 d (1–35), suggesting that most pts can resume treatment after a 1-week cycle delay. A comparable proportion of any grade neutropenia was observed in pts with or without prior CT (prior CT 88.4% vs no prior CT 85.4%). There was no difference in the rate of G3/G4 neutropenia in the older pts (&amp;gt;65 yrs, 51% vs ≤65 yrs, 57%) in P+F arm. Concurrent G≥3 infections occurred in 1% of pts with G≥3 neutropenia (2/192 pts). Febrile neutropenia occurred in 0.6% of pts in both arms. 21% of pts had dose reductions and 45% had dose interruption due to neutropenia. Dose intensity was maintained at 89.7% for P. Serious adverse events (SAEs) were reported in 9.6% of pts on P+F and in 14% of pts on PLB+F. The most common SAEs on P+F were pulmonary embolism (0.9%) and pyrexia (0.9%). Safety analyses with longer follow-up (data cut off, March 2015) are ongoing and will be presented. Conclusions: Findings suggest P+F has a favorable safety profile characterized mainly by asymptomatic hematologic toxicity. Overall SAE rates were low and comparable between the 2 arms. Palbociclib-related neutropenia differs from that seen with CT, consistent with proposed mechanism of action, in that it is not commonly associated with fever, and can be effectively managed by a dose interruption or cycle delay. Funding: Pfizer, Inc. Citation Format: Verma S, DeMichele AM, Loi S, Ro J, Colleoni M, Iwata H, Harbeck N, Stearns V, Cristofanilli M, Huang Bartlett C, Schnell P, Zhang K, Thiele A, Turner NC, Rugo HS. Updated safety from a double-blind phase 3 trial (PALOMA-3) of fulvestrant with placebo or with palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-03.

Plasma and intracellular ribavirin concentrations are not significantly altered by abacavir in hepatitis C virus-infected patients.

The objective of this study was to evaluate the effects of abacavir on intracellular ribavirin triphosphate and plasma ribavirin trough concentrations. Hepatitis C virus-infected subjects who had been cured or failed prior treatment were randomized to 8 weeks of ribavirin alone (N = 14; weight-based dosing) or weight-based ribavirin + abacavir (N = 14; 300 mg orally every 12 h). Ribavirin trough concentrations were measured on days 14, 28, 42 and 56; PBMCs for ribavirin triphosphate determination were sampled on days 28 and 56, pre-dose and at 6 and 12 h post-dose. ClinicalTrials.gov: NCT01052701. Twenty-six subjects completed the study (24 males, 17 Caucasians, median age 52 years); 2 were excluded for missed pharmacokinetic visits. Fourteen subjects received ribavirin + abacavir and 12 received ribavirin alone. Mean ± SD plasma ribavirin trough concentrations (μg/mL) on days 14, 28, 42 and 56, respectively, were not significantly different with coadministration of abacavir (1.54 ± 0.60, 1.93 ± 0.54, 2.14 ± 0.73 and 2.54 ± 1.05) compared with ribavirin alone (1.48 ± 0.32, 2.08 ± 0.41, 2.32 ± 0.47 and 2.60 ± 0.62) (P > 0.40). Mean ribavirin triphosphate intracellular concentrations (pmol/10(6) cells) on days 28 and 56, respectively, did not differ statistically between abacavir users (11.98 ± 9.86 and 15.87 ± 12.52) and non-users (15.91 ± 15.58 and 15.93 ± 12.69) (P > 0.4). Adverse events were mild or moderate, except for three grade 3 occurrences of transaminitis, cholecystitis and low absolute neutrophil count that resolved and were judged not attributable to study medications. Abacavir did not significantly alter ribavirin or ribavirin triphosphate concentrations.

Neutropenia in dogs: etiology and prognostic factors

The aim of this retrospective study was to evaluate frequency, prognostic factors, and differences for various etiologies of neutropenia in dogs. A total of 391 dogs with neutrophil counts <2.78x109/l (January 2008 to December 2012) were included and, depending on the etiology of neutropenia, assigned to seven diagnostic groups: nonbacterial infectious disease, increased demand due to marked inflammation, drug-associated, bone-marrow diseases, immune-mediated, physiologic, miscellaneous. Absolute neutrophil counts, evidence of neutrophil toxicity or left shift, case history, rectal temperature, hospitalization, and survival were compared among groups. Increased demand due to marked inflammation (90/391, 23%) and nonbacterial infectious disease (70/391, 18%) were the most common causes for neutropenia, followed by drug-associated neutropenia (43/391, 11%) and bone-marrow disease (32/391, 8%). Immune-mediated and physiologic neutropenia (both 16/391, 4%) were uncommon. Almost one third (124/391, 32%) of dogs were assigned to the miscellaneous group. Absolute neutrophil counts were significantly higher (p<0.01) in dogs of the physiologic and miscellaneous groups than in the other groups. Dogs with immune-mediated neutropenia or nonbacterial infectious disease displayed significantly lower absolute neutrophil counts than dogs with neutropenia due to an increased demand (p<0.001) and were most commonly referred with a history of fever (11/16, 69%) or gastrointestinal signs (52/70, 74%), respectively. Neutrophil toxicity and left shift were most commonly associated with an increased demand due to marked inflammation (60/90 and 25/90, 67% and 28%, respectively) and the mortality rate was highest in this group (32/90, 36%). Neutrophil toxicity and left shift are associated with an increased demand due to marked inflammation and may indicate a poor prognosis. The lower the absolute neutrophil count, the greater the probability of an immune-mediated neutropenia. Neutropenia should be assessed in context with case history, clinical examination, and neutrophil morphology.

FOLFOX chemotherapy can safely be given to neutropenic patients with early-stage colorectal cancer for higher dose intensity and fewer visits.

How does giving adjuvant FOLFOX chemotherapy to patients with early-stage colorectal cancer (ESCRC) regardless of the day-before absolute neutrophil counts (ANC) effect chemotherapy-induced febrile neutropenia (CIFN) rates, received dose intensity (RDI), and chemotherapy cycle delay? Does an ANC level predict future neutropenia? A retrospective chart review was conducted on all patients receiving adjuvant chemotherapy for ESCRC at a mid-sized community hospital in Toronto, Ontario, Canada between April 2005 and May 2014. All patients were under one medical oncologist. Day-before CBC data were collected along with other patient characteristics. CIFN was confirmed by hospital records. Inclusion criteria were met by 132 patients. Overall, 1074cycles of chemotherapy were analyzed. Six episodes of CIFN were observed. There was a significant difference in the average day-before ANC between patients who developed CIFN (1.4×10(9)/L, 95% CI 0.76-2.0×10(9)/L) and those who did not (2.9×10(9)/L, 95% CI 2.8-3.0×10(9)/L, p=0.03). The RDI for oxaliplatin was 0.95 and for 5-fluorouracil (5-FU) was 0.96. A total of 170cycles were given at day-before ANC <1.5×10(9)/L (range 0.1×10(9)/L-1.4×10(9)/L), and 24 were delayed for 1week for hematologic reasons. Cycles given with grade 2 neutropenia predicted higher grades of neutropenia with a sensitivity of 0.22 (95% CI 0.12-0.38). Adjuvant FOLFOX chemotherapy may be given in the setting of low day-before ANC to patients with ESCRC. The benefits include higher RDI and a reduced number of clinic visits for the patient.

Inflammatory indices in meconium aspiration syndrome

Meconium aspiration syndrome (MAS) is linked to inflammation, but data on the patterns of hematological indices and C-reactive protein (CRP) in MAS are lacking. The aim of the study was to evaluate CRP, white blood cell count (WBC), absolute neutrophil count (ANC), and immature-to-total neutrophil ratio (IT-ratio) in MAS and to assess their association with disease severity. Retrospective cross-sectional study including 239 consecutively admitted neonates with MAS to a level III NICU. Neonates with early onset sepsis were excluded. Results Neonates with severe MAS (invasive mechanical ventilation for <7 days) and very severe MAS (invasive mechanical ventilation for ≥7 days or high frequency ventilation or ECMO) had higher CRP and IT-ratio compared to neonates with non-severe MAS (no invasive mechanical ventilation) during the first 2 days of life (CRP: 13.0 and 40.9 vs. 9.5 mg/L, P = 0.039 and <0.001, respectively) and neonates with very severe MAS had lower WBC and ANC. All four inflammatory indices correlated significantly with duration of invasive mechanical ventilation, duration of respiratory support and with length of hospital stay, arterial hypotension, and persistent pulmonary hypertension. Neonates with all four inflammatory indices beyond the normal range had a more than 20-fold increase in risk for very severe MAS. High CRP and IT-ratio and low WBC and ANC values were closely linked to a more severe course of MAS during the early phases of the disease. These findings reflect the role of inflammation in the pathogenesis of MAS. Pediatr Pulmonol. 2016;51:601-606. 2015 Wiley Periodicals, Inc.

Clozapine Use Varies From State to State

Clozapine Use Varies From State to State

Optimizing outcomes in clozapine rechallenge following neutropenia: a cohort analysis.

Certain patients with treatment-refractory schizophrenia may be rechallenged with clozapine following previous neutropenia. Evidence guiding patient selection and the effectiveness of lithium and granulocyte-colony stimulating factor (G-CSF) in rechallenge is limited, and factors associated with successful outcomes are unclear. Outcomes were studied in patients rechallenged with clozapine at a tertiary referral center between January 2007 and December 2013, following 1 or more previous trials terminated due to neutropenia, defined as an absolute neutrophil count (ANC) < 1.5 × 10(9)/L. Demographic characteristics, details of each clozapine trial including ANC, and coprescribed medication were extracted, and factors associated with rechallenge outcomes were examined. Nineteen patients underwent clozapine rechallenge following previous neutropenia; 4 (21%) experienced further neutropenia, 2 of which developed agranulocytosis. Compared to successfully rechallenged patients, unsuccessfully rechallenged patients were significantly older (t = 2.10, P = .05), experienced onset of neutropenia sooner (W = 10.0, P = .03), and were more commonly coprescribed valproate. In addition to 5 patients with benign ethnic neutropenia (BEN), 8 patients not of an ethnicity associated with BEN also had idiopathic low neutrophil counts at baseline; lithium and G-CSF coprescription facilitated successful rechallenge in these patients. In this selected population, the initial neutropenia was unlikely to be related to clozapine in a substantial proportion of cases. This group was successfully rechallenged following careful consideration of the risks and benefits, and lithium and G-CSF contributed to allowing continued clozapine therapy. In addition to black patients, other ethnic groups can have persistently low ANC unrelated to clozapine.

Clinicopathologic, Immunophenotypic, Cytogenetic, and Molecular Features of γδ T-Cell Large Granular Lymphocytic Leukemia: An Analysis of 14 Patients Suggests Biologic Differences With αβ T-Cell Large Granular Lymphocytic Leukemia. [corrected

T-cell large granular lymphocytic (T-LGL) leukemia is a rare disorder in which the neoplastic cells usually express the αβ T-cell receptor (TCR). To determine the significance of γδ TCR expression in this leukemia, we compared the clinicopathologic, immunophenotypic, and genetic features of patients with T-LGL leukemia expressing γδ TCR or αβ TCR. We used the World Health Organization classification criteria to confirm the diagnosis. All patients were diagnosed and treated at our institution. We identified 14 patients with γδ T-LGL leukemia, 11 men and three women; six (43%) patients had a history of rheumatoid arthritis, 10 (71%) had neutropenia, four (29%) had thrombocytopenia, and three (21%) had anemia. Eight (67%) of 12 patients had a CD4-/CD8- phenotype, and four (33%) had a CD4-/CD8+ phenotype. The median overall survival was 62 months. Patients with γδ T-LGL leukemia were more likely to have rheumatoid arthritis (P = .04), lower absolute neutrophil count (P = .04), lower platelet count (P = .004), and a higher frequency of the CD4-/CD8- phenotype (P < .0001). However, there was no significant difference in overall survival between the two groups (P = .64). Although patients with γδ and αβ T-LGL leukemia show some different clinical or phenotypic features, overall survival is similar, suggesting that γδ TCR expression does not carry prognostic significance.

Safety and Efficacy of Combined Treatment with Pegylated Interferon Alpha-2b and Ribavirin for HCV Genotype 4 in Children.

Combined treatment with pegylated interferon (PEG-IFN)-α2b and ribavirin (RBV) is the only currently approved treatment for hepatitis C virus (HCV) infection in children. The aim of this study was to assess the safety and efficacy of combined treatment with PEG-IFN-α2b and RBV in Egyptian children and adolescents with genotype 4 (GT4) HCV infection. The study included 66 patients (3-17 years of age), of both sexes, infected with HCV GT4, treated with PEG-IFN-α2b (60 μg/m(2)), subcutaneously once weekly plus RBV (15 mg/kg/day) in 2 divided oral doses. Efficacy was assessed by achievement of sustained virological response (SVR). Safety was assessed by questionnaires directed to the patients at specific intervals, growth assessment and laboratory tests. SVR was achieved in 28 patients (42.4%). Nonresponders had significantly commoner history of treated malignancies (P = 0.03), baseline lower absolute neutrophil count (ANC; P = 0.009), higher gamma glutamyl transpeptidase (GGT; P = 0.003), and higher viral load (P = 0.03). Fever was the most frequently reported side effect occurring in 98.5% of the patients followed by musculoskeletal symptoms. Neutropenia was observed in 36 patients (54.6%) and necessitated treatment discontinuation in 1 patient. Decline in both weight and height percentiles was observed in 70% of children who received the combined therapy for a total of 48 weeks. In conclusion, the currently available treatment for HCV GT4 in pediatric patients has modest SVR with numerous adverse events necessitating meticulous monitoring to optimize care of the patients. Side effects could be managed with dose modifications and specific treatment when necessary.

Neutrophil and Lymphocyte Counts as Clinical Markers for Stratifying Low-Risk Prostate Cancer

IntroductionThe neutrophil-to-lymphocyte ratio (NLR) has emerged as a ubiquitous prognostic biomarker in cancer-related inflammation, specifically in patients with metastatic castration-resistant prostate cancer (PCa). We evaluated the clinical utility of the preoperative NLR, absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) as a risk stratification tool for patients with low-risk PCa. Materials and MethodsWe identified 217 low-risk PCa patients with preoperative hematologic data who had met the criteria for active surveillance but had undergone robot-assisted radical prostatectomy at our institution from 2006 to 2015. Logistic regression models were constructed to determine whether the baseline NLR, ANC, and ALC were associated with upstaging, upgrading, and biochemical recurrence (BCR). Survival analyses were performed using the Kaplan-Meier method. ResultsOn multivariate analysis, a higher prostate-specific antigen level (odds ratio [OR], 1.554; 95% confidence interval [CI], 1.148-2.104), a greater number of positive cores (OR, 2.098; 95% CI, 1.043-2.104), and a higher ALC (OR, 4.311; 95% CI, 1.258-14.770) were associated with upstaging. More importantly, the 5-year biochemical recurrence-free survival was significantly lower in the high ANC group (ANC > 4.0 × 109/L) compared with that of the low ANC group (P = .011). The NLR was not associated with upstaging, upgrading, or BCR in our study cohort (P = .368, P = .573, and P = .504, respectively). The only significant association with upgrading was patient age (OR, 1.106; 95% CI, 1.043-1.173). ConclusionNLR was not useful in predicting adverse pathologic outcomes in our patients with low-risk PCa. However, relative neutrophilia and lymphocytosis might indicate an early manifestation of harboring a more aggressive PCa.

Severe neutropenia in children after renal transplantation: incidence, course, and treatment with granulocyte colony-stimulating factor.

Infections are an important cause of morbidity and mortality in solid organ transplant recipients. Neutrophils play a crucial role in the initial host defense against bacterial pathogens. Neutropenia is not uncommon after renal transplantation in adults; however, there are scarce published data in children. We conducted a historical cohort study to evaluate the incidence, clinical course, and management of severe neutropenia after renal transplantation in children. In a single-center study, we collected clinical and laboratory data on all children (<20 years) who underwent renal transplantation from January 2005 to March 2014. All post-transplantation blood counts were reviewed; the lowest absolute neutrophil count was recorded and correlated with clinical information and other laboratory findings. Of the 72 patients studied, 46 (64%) had at least one episode of neutropenia [absolute neutrophil count (ANC) <1500/μl] during the study period, 16 of whom (22%) had severe neutropenia (ANC < 500/μl), 2-11 months (median, 3.5) after renal transplantation. Work-up for viral infection or malignancy was performed. Initial management included dose decrease and subsequent discontinuation of antimetabolite, stopping co-trimoxazole and valganciclovir. Bone marrow aspiration in four children revealed normal marrow cellularity in all cases, with myelocyte maturational arrest in two. Eight children (11%) were treated with granulocyte colony-stimulating factor (G-CSF) (5 mcg/kg/day) 1-4 doses (median, 2), with excellent response in all and no adverse effects. Eight children presented with fever during severe neutropenia, and were treated with empiric antibiotics. Mycophenolate/azathioprine were resumed in all patients unless contraindicated (pre-existing BK viremia -1, PTLD -1). Recurrence of neutropenia was seen in five patients, only one of whom required further treatment with G-CSF. Graft function was preserved during and after resolution of neutropenia. Post-transplant neutropenia in children is common, and mostly occurs in the first few months. Its etiology is probably primarily a result of the combination of immunosuppressive agents and prophylactic treatment of infections in the early post-transplant period. Decreasing immunosuppressive or antimicrobial medications carries the risk of acute rejection or infection. Off-label treatment with G-CSF may present a safe and effective alternative.