Improvement Of Neutropenia Research Articles

Improvement of neutropenia in 2 adolescent cases treated with empagliflozin for glycogen storage disease type Ib

Neutropenia and elevated concentrations of hepatic transaminases often lead to referrals from emergency or outpatient departments to relevant specialists to diagnose underlying inborn errors of metabolism. Glycogen storage disease type (GSD) Ib, a rare congenital disorder of glucose metabolism caused by the SLC37A4 gene mutations, shows various manifestations, including persistent neutropenia and elevated hepatic transaminases. Empagliflozin has demonstrated its efficacy in treating GSD Ib-associated neutropenia by reducing the entry of 1,5-anhydroglucitol-6-phosphate into the neutrophils. This article reports successful empagliflozin therapy for GSD Ib-related neutropenia in 2 Korean adolescents. Diagnosing GSD Ib is complex and usually initiated by a referral from emergency or outpatient departments when there is a high index of suspicion. Once diagnosed, empagliflozin shows promising outcomes in restoring counts and function of the neutrophils without severe adverse effects in children with GSD Ib, supporting it as a safe and effective therapeutic option for GSD Ib-associated neutropenia.

T-Cell Lgll of the Γδ Subtype: Clinically Relevant Fact or Academically Interesting Finding?

Large granular lymphocyte leukemia (LGLL) is a rare group of mature T and NK cell lymphoproliferative disorders, with an annual incidence of 0.2 - 0.72 cases per 1 million individuals. Median age of onset is 65, with case prevalence roughly equivalent between sexes. T-Cell LGLL (T-LGLL) makes up 85-91% of cases. The majority of T-LGLL clones express Tαβ, with only 5% of cases expressing Tγδ. Outcomes and treatment data on this subtype is limited. Recent observational data suggest reduced overall survival (OS), increased incidence of cytopenias and associated autoimmune diseases, and favorable response to first line therapy with cyclosporine, in comparison to the Tαβ subtype. Here, we summarize disease biology and clinical presentation and provide review of recent literature describing clinical course and treatment options in the context of a patient case. A woman in her early 70's with osteoporosis, asthma and hypertension presented to hematology after she was found to have leukocytosis of 12.1* 103/µL during routine lab work. CBC w/differential showed lymphocytosis of 11.0* 103/µL with absolute neutrophil count of 496 *103/µL and thrombocytopenia (121* 103/µL). She was asymptomatic without history of malignancy or autoimmune disease, prior available labwork was normal and physical exam was unremarkable. Peripheral smear showed atypical lymphocytes, with flow cytometry demonstrating 50.45% clonality with CD2+, CD3+, CD4-, CD7+, CD8 +/- , CD16+, CD 56-, CD57+/-, Tγδ + phenotype. Bone marrow biopsy demonstrated hypercellular (70%) marrow with scattered lymphoid aggregates with clonal infiltration of 20% core cellularity by CD3 immunohistochemistry. Bone marrow flow demonstrated the T-Cell phenotype seen in peripheral blood. T-Cell clonality study demonstrated TCR gamma chain rearrangement. PET/CT showed mildly increased FDG uptake throughout bone marrow. Next-Generation Sequencing confirmed mutations of STAT3 (D661Y), ASXL1, and TET2. There is conflicting data on whether Tγδ positivity portends reduced OS compared to Tαβ. Observational studies show that Tγδ is more frequently symptomatic and conveys higher risk of cytopenias. Not all cases require treatment. Treatment is usually prompted by single-lineage cytopenias. First line single agent therapy with methotrexate (MTX), cyclosporine, and cyclophosphamide have shown similar overall response rates of 40-50%, though STAT3 mutated disease is associated with better response to MTX. STAT3 mutations are associated with more severe cytopenias, more frequent autoimmune/inflammatory disorders, and more frequently required therapy, however neither STAT mutations nor cytopenias convey decreased OS in Tγδ disease. STAT3 and STAT5b mutations occur in 40% of all LGLL cases, with STAT3 mutations associated with neutropenia and rheumatoid arthritis. Nearly two thirds of STAT3 genetic mutations are Y640F and D661Y. Our patient was initiated on prednisone, though due to poor tolerance was transitioned to MTX titrated to 12.5 mg weekly. She has remained on this dose with good tolerability for 18 months with resolution of lymphocytosis and improvement in neutropenia. T-LGLL has an OS of 9 years. Rarity of Tγδ disease has limited the ability to generate subtype specific survival data. The largest retrospective study to date included 137 Tγδ patients across 8 centers and provided a signal that Tγδ disease may predict reduced OS compared to the Tαβ subtype, however data was limited by disparate median follow-up time amongst cohorts due to high rates of censorship in the Tγδ cohort. Median OS was not reached at median follow up time of 48 months. This trend would be clinically expected given that Tγδ subtype has been consistently associated with severe cytopenias and autoimmune diseases, but should not be accepted until higher quality evidence is generated over longer median follow-up times. The same study found better responses to cyclosporine as first line therapy, an interesting observation as MTX has been generally accepted as first line therapy based on predominantly retrospective studies, though these studies did not stratify treatment responses by TCR phenotype. These findings underscore the need for prospective studies characterizing Tγδ specific disease course, survival analyses and treatment response.

A clinical evaluation of efficacy and safety of cefepime monotherapy versus piperacillin-tazobactam in patients of paediatric age group with febrile neutropenia in a tertiary care centre of north India

To evaluate clinically the efficacy and safety in northern India of cefepime monotherapy versus piperacillin-tazobactam in patients of paediatric age group with febrile neutropenia. Children aged ≤18 years admitted febrile with chemotherapy-induced neutropenia were randomised into two groups comprising 20 cases in each group viz. CEF (receiving cefepime only) and PIP-TAZO (receiving piperacillin-tazobactam). Based on clinical and laboratory tests, patients were classified into: microbiologically documented infections (MDI); clinically documented infections (CDI); and unexplained fever (UF). They were assessed for clinical signs and symptoms as well as laboratory parameters at the time of enrolment and subsequently on days 3 and 7. Incidence of MDI, CDI and UF were 22.5%, 47.5% and 30%, respectively. The mean duration of neutropenia (in days) was 5.45 ± 2.1 in the PIP-TAZO group and 5.5 ± 1.5 in the CEF group (P = 0.305). The success rate defined as clearing infection effectively and improvement of neutropenia was comparable (P = 0.705). There was a mortality rate of 20% in the PIP-TAZO group as compared to 10% in the CEF group. We conclude that cefepime monotherapy and piperacillin-tazobactam are equally efficacious and safe in treating patients with febrile neutropenia. Empirical monotherapy with cefepime would prevent an unnecessary extra economic burden as well as avoiding the serious adverse or toxic effects of multi-drug regimes, especially in low- and middle-income countries.

Recurrent Lung Abscesses during Chemotherapy in Non-neutropenic Patient with Limited Stage Small Cell Lung Cancer: A Case Report and Review

Background: Small cell lung cancer (SCLC) represents 14% of all lung cancer cases. The current standard of care for limited stage SCLC is the chemotherapy combination of EP (etoposide, cisplatin) with concomitant radiotherapy. Treatment protocol is tolerated well and is associated with few side effects.Case Description: 58 y.o. lady diagnosed to have limited stage SCLC in our institute in November 2013. She was planned for concomitant chemoradiotherapy (CCRT). She started initially on chemotherapy protocol EP. On day 12 of cycle 2, the patient complained of Fever, excessive cough. CT thorax showed newly developed peripherally situated pulmonary abscess. She was kept in with IV antibiotics, and her condition was improved thereafter. Then she was started on CCRT, with cycle 3 EP. On day 6 of her cycle 3, she developed fatigue, poor general condition, high fever, cough and neutropenia. She was admitted as neutropenic sepsis, with improvement of neutropenia after only 1 shot of short acting GCSF. Sputum culture showed Klebsiella pneumonia. CT Thorax showed new lung abscess in the Left ligula. She was treated by IV antibiotic for 10 days. Her condition was improving thereafter and she was returned back to radiotherapy, as well as Cycle 4 EP. Currently, she finished her treatment since 1 month with no complication related to treatment protocol. Discussion: Although few, studies attributed the reason for lung abscess development to leuconeutropenia in some patients, and to relatively large primary tumour size in other patients. Conclusion: Many reasons may explain the development of lung abscess in non-neutropenic patient including chemotherapy side effect, underlying chest condition, and relatively large primary tumour size.

Therapeutic implications of variable expression of CD52 on clonal cytotoxic T cells in CD8+ large granular lymphocyte leukemia

T-cell large granular lymphocytic leukemia is a clonal proliferation of cytotoxic T-lymphocytes which often results in severe cytopenia. Current treatment options favor chronic immunosuppression. Alemtuzumab, a humanized monoclonal antibody against glycophosphatidylinositol-anchored CD52, is approved for patients refractory to therapy in other lymphoid malignancies. We retrospectively examined treatment outcomes in 59 patients with CD8+ T-cell large granular lymphocytic leukemia, 41 of whom required therapy. Eight patients with severe refractory cytopenia despite multiple treatment regimens had been treated with subcutaneous alemtuzumab as salvage therapy. Flow cytometry was used to monitor expression of glycophosphatidylinositol-anchored CD52, CD55, and CD59 as well as to characterize T-cell clonal expansions by T-cell receptor variable beta-chain (Vbeta) repertoire. Analysis of the effects of alemtuzumab revealed remissions with restoration of platelets in one of one patient, red blood cell transfusion independence in three of five patients and improvement of neutropenia in one of three, resulting in an overall response rate of 50% (4/8 patients). Clonal large granular lymphocytes exhibited decreased CD52 expression post-therapy in patients refractory to treatment. Samples of large granular lymphocytes collected prior to therapy also unexpectedly had a significant proportion of CD52-negative cells while a healthy control population had no such CD52 deficiency (p=0.026). While alemtuzumab may be highly effective in large granular lymphocytic leukemia, prospective serial monitoring for the presence of CD52-deficient clonal cytotoxic T-lymphocytes should be a component of clinical trials investigating the efficacy of this drug. CD52 deficiency may explain lack of response to alemtuzumab, and such therapy may confer a survival advantage to glycophosphatidylinositol-negative clonal cytotoxic T-lymphocytes.

Alemtuzumab Shows Significant Efficacy in T-LGL Leukemia and Refractory Cases Are Due to GPI-Deficiency of LGL Clones.

T cell large granular lymphocytic (LGL) leukemia is a clonal proliferation of cytotoxic T-lymphocytes (CTLs) often resulting in severe cytopenia, including neutropenia and anemia. Clinical observations and laboratory data suggest that LGL evolves in the context of initially normal polyclonal immune responses. Current treatment options favor chronic immunosuppression as high-dose chemotherapy is mostly ineffective. Since 2002 we have diagnosed and treated 75 patients (pts) with LGL leukemia, 45 of whom required therapy. We have identified 8 pts with severe refractory cytopenia despite multiple treatment regimens and who in the course of their care received salvage therapy with subcutaneous alemtuzumab (total dose 60-120 mg in triweekly injections of 10 mg). Previous therapies involved cyclosporine (7/8), cyclophosphamide (2/8), methotrexate (2/8), prednisone (5/8), rituximab (4/8) and high-dose chemotherapy (4/8) including CHOP, ifosfamide, fludarabine, and autologous stem cell transplantation. Analysis of the effects of alemtuzumab therapy revealed remissions with restoration of platelets in 1/1, red blood cell transfusion independence in 3/5 patients and improvement of neutropenia in 1/3 resulting in an overall response rate of 4/8 pts (50%). In the course of analysis we explored cases refractory to alemtuzumab, a monoclonal antibody which recognizes glycosyl phosphatidylinositol (GPI) anchored CD52 antigens ubiquitously expressed on most leukocytes. Previously, the evolution of CD52 deficient T and B cells has been described following alemtuzumab therapy for CLL. Flow cytometric analysis of archived cells collected post therapy demonstrated that clonal CTLs exhibit decreased CD52 expression within the CD8+CD3+CD57+ cell compartment. Vb TCR repertoire analysis by flow also showed that the CD8+ clonal LGL cells expressing a restricted Vb region of the TCR were the predominant CD52 negative cells. Based on this finding, we tested samples collected prior to therapy and unexpectedly found a significant proportion of CD8+CD3+CD57+ cells were CD52 negative before alemtuzumab therapy. In one pt, biclonal LGL was discovered with both clones (one Vb7.1+ and the other Vb3+) lacking expression of CD52 on ~20% of cells. Following alemtuzumab therapy not resulting in a hematologic response, the Vb 7.1+ clone dominated the T cell repertoire, accounting for 92.8% of CD8 cells. Furthermore, 85.7% of these cells lacked CD52 expression, suggesting that alemtuzumab selected for CD52 negative cells. To assess the prevalence of LGL cases with deficient CD52 expression we prospectively analyzed 12 LGL pts. All pts were positive for TCR-g rearrangement and showed expansion of a CD8+CD3+CD57+ Vb restricted CTL population. In 9/12 LGL pts varying amounts of CD52 deficient CTLs were identified while virtually all CD8 cells from healthy controls (n=12) expressed CD52 (p=.006). Further analysis of CD52 deficient cells demonstrated the absence of other GPI linked proteins CD55 and CD59. Previously, GPI-deficient lymphocytes observed after alemtuzumab therapy were shown to contain a wild type PIG-A gene. In the absence of a mutation such as in paroxysmal nocturnal hemoglobinuria, we conclude that deficient expression of GPI-linked proteins is rather due to downmodulation of genes associated with synthesis of a GPI anchor. Reduced mRNA levels of the PIG-A gene have been reported in memory cells suggesting that GPI negativity of LGL cells in some patients may be due to a higher proportion of memory cells within the leukemic cell population. In sum, we conclude that while alemtuzumab may be highly effective in LGL leukemia, prospective monitoring for the presence of CD52 deficient clonal CTLs may be necessary prior to and during therapy.

Darbepoetin 500 mcg Q3W, Alone or in Combination with Peg-Filgrastim, in Low/Int1 IPSS Risk Myelodysplastic Syndromes Unresponsive to Recombinant Erythropoietin.

Darbepoetin (DPO), a long acting erythropoiesis stimulating protein, is effective in inducing erythroid responses in 40–71% of anemic patients with myelodysplastic syndromes (MDS) when given at fixed doses of 150–300 mcg once-a-week. Of interest, some of these responses have been reported in MDS patients previously treated with (and occasionally unresponsive to) recombinant erythropoietin (r-EPO). We aimed to explore, on a compassionate basis, the effects of a higher DPO dose, administered with longer intervals, specifically in this last setting of patients. A single s.c. injection of DPO at the dose of 500 mcg s.c. was given every 3 weeks (Q3W) in fifteen anemic MDS patients, who had a history of an unsuccessful prior treatment with alpha or beta r-EPO (total weekly doses of r-EPO received: 30.000–80.000 U, for at least 8 weeks), both primary resistant or with loss of efficacy after an initial response. Informed consent was obtained in all cases. Nine patients were male, six female; mean age was 71 years (range 62–82). According to WHO classification, there were 5 RA, 3 RARS, 6 RCMD and 1 RCMD-RS. IPSS score was low in 6 patients and intermediate-1 in the remaining 9 subjects. Baseline Hb levels ranged from 6.2 to 9.1 g/dl, twelve patients being transfusion-dependent. All patients were treated with at least 3 DPO doses (nine weeks of therapy) and were evaluable for short term response and safety. No relevant adverse effect attributable to DPO was recorded. According to recently revised IWG criteria, three patients (20%) achieved an erythroid response. Transfusion-independence was obtained in one of two transfusion-dependent responders. All responses occurred after 2 doses of DPO in patients with baseline endogenous EPO below 200 miu/ml, two of whom previously treated with r-EPO 10.000 U s.c. t.i.w, while one had received 40.000 U s.c. b.i.w. Erythroid responses were maintained prolonging intervals between two DPO administrations up to 6 weeks. Based on the previously described possible synergism between r-EPO and myeloid growth-factors in MDS and to the concomitant presence of symptomatic neutropenia, five patients non-responding to DPO alone received Peg-filgrastim, a novel, pegylated form of granulocyte-colony stimulating factor (G-CSF) with prolonged terminal half-life, at the dose of 6 mg s.c. every 3 weeks, in combination with DPO, for an additional period of 9 weeks. The treatment was well tolerated, but no improvement in Hb levels or reduction in transfusional support was observed. A significant increase in peripheral blood WBC count occurred in all patients treated with Peg-filgrastim. In this preliminary experience, DPO given at the fixed dose of 500 mcg Q3W was effective in some anemic MDS patients considered unresponsive to r-EPO. However, it should be taken into account the fact that at least two of responders had probably previously received r-EPO at sub-optimal doses (less than 40.000 U per week). The adjunct of Peg-filgrastim in this setting of patients resulted in an improvement of neutropenia, without effects on Hb levels.

Felty's syndrome.

Felty's syndrome (FS) comprises a triad of rheumatoid arthritis (RA), neutropenia and splenomegaly, occurring in less than 1% of RA patients. Clinically it is characterized by severe joint destruction contrasting with moderate or absent joint inflammation and severe extra-articular disease, including a high frequency of rheumatoid nodules, lymphadenopathy, hepatopathy, vasculitis, leg ulcers, skin pigmentation etc. Recurrent bacterial infections are mostly due to the severe, otherwise unexplained neutropenia. The cause of neutropenia lies in both decreased granulopoiesis and increased peripheral destruction of granulocytes. Recurrent infections may lead to increased mortality. Spontaneous remission of the syndrome also occurs. Over 95% of FS patients are positive for rheumatoid factor (RF), 47-100% are positive for antinuclear antibody (ANA), and 78% of patients have the HLA-DR4*0401 antigen. Some 30% of FS patients have large granular lymphocyte (LGL) expansion. LGL expansion associated with uncomplicated RA is immunogenetically and phenotypically very similar to but clinically different from FS. Neutropenia of FS can be effectively treated with disease-modifying anti-rheumatic drugs (DMARDs), the widest experience being with methotrexate (MTX). Results of treatment with granulocyte colony-stimulating factor (G-CSF) are encouraging, but there is no experience with other biological agents. Splenectomy results in immediate improvement of neutropenia in 80% of the patients, but the rate of infection decreases to a lesser degree.

GM-CSF and G-CSF in Felty's syndrome

The risk of infection is increased in patients with Felty's syndrome, neutropenia being one of the main reasons for the susceptibility to infection. We report the case of a 56-year-old patient with Felty's syndrome in whom successive therapy with GM-CSF, splenectomy, and G-CSF was tried because of recurrent severe infections. Therapy with GM-CSF and G-CSF resulted in improvement of neutropenia and in successful treatment of cutaneous and pulmonary infections.

Improvement of neutropenia and neutrophil dysfunction by granulocyte colony-stimulating factor in a patient with glycogen storage disease type Ib

Patients with glycogen storage disease type Ib (GSD Ib) suffer from recurrent bacterial infections due to neutropenia and neutrophil dysfunction. To improve the quality of life in a 9-year-old boy with GSD Ib, we subcutaneously administered recombinant human granulocyte colony-stimulating factor (G-CSF). Daily injections of 100 micrograms/m2 of G-CSF significantly increased absolute neutrophil counts and augmented neutrophil mobility. The patient was then treated with 70 and 100 micrograms/m2 of G-CSF daily and twice-weekly. The treatment maintained absolute neutrophil counts at significantly higher levels than those without treatment for 22 months and markedly decreased the frequency of infections and the necessity for hospitalisation. Weekly injections of 70 micrograms/m2 of G-CSF were less efficient. No adverse effects were observed during treatment. These findings indicate that daily and twice-weekly treatment with G-CSF of long duration are safe and effective for patients with GSD Ib. G-CSF may be a useful therapeutic agent in patients with neutrophilic impairment as a consequence of a metabolic disorder.

Lithium for treatment of neutropenia in glycogen storage disease type Ib

In addition to the characteristic clinical and biochemical features of glucose-6-phosphatase deficiency, patients with glycogen storage disease type Ib have varying degrees of granulocytopenia and impaired neutrophil function) Frequent cutaneous and mucocutaneous infections, predominantly with staphylococci, are common? Dietary therapy does not influence the neutropenia. Continuous prophylaxis with cotrimoxazole is recommended in neutropenic GSD-Ib? Some improvement of neutropenia in single cases of GSD-Ib has been reported during treatment with triamcinolone, hydrocortisone, or glucagon) Granulocytosis is a frequent side effect of lithium therapy for psychiatric disorders. 4 The stimulating effect of lithium salts on granulopoiesis has been used therapeutically in various idiopathic and congenital neutropenia syndromes, in neutropenia associated with Felty syndrome, and with chemotherapy:.5 In GSD-Ib, a positive effect of lithium on granulopoiesis has been demonstrated in vitro; lithium chloride enhanced the production of colony-stimulating factor, an essential modulator of granulocyte maturation, in cultured monocytes of a child with GSD-Ib. 6 Recently, Biihrdel et al. 7 found an amelioration of neutropenia as well as improved granulocyte maturation in bone marrow in a child with GSD-Ib. We report our experience with lithium treatment of severe neutropenia in a girl with GSD-Ib.

Hairy cell leukemia. Durability of response to splenectomy in 26 patients and treatment of relapse with androgens in six patients.

Twenty-three of 26 patients with hairy cell leukemia evaluable for response to splenectomy had significant improvement in anemia, thrombocytopenia, and/or neutropenia. Eight of the 23 had a recurrence of cytopenia after a median response duration of 4 to 5 months (range, 1-22). The remaining 15 patients did not have a recurrence of cytopenia at 20 months median follow-up (range, 1-76). Six patients with postsplenectomy cytopenia were given androgenic steroids. Two of the six had an improvement in anemia and thrombocytopenia, and a third patient had an improvement in neutropenia. It was concluded that, although most patients with hairy cell leukemia have initial improvement in cytopenia with splenectomy, a significant number of them either fail to respond or have recurrent cytopenia after initial response to splenectomy. A trial of androgenic steroids is a reasonable therapeutic option in these patients. Alternative therapies are reviewed and recommendations made.