Immunoglobulin Replacement Therapy in Chronic Lymphocytic Leukaemia patients with hypogammaglobulinaemia and infection; analysis of total national utilisation data in Australia 2008-2013

Objectives To analyse total national utilisation of immunoglobulin (Ig) replacement therapy (IgRT) for Chronic Lymphocytic Leukaemia patients with acquired hypogammaglobulinaemia and severe and/or recurrent bacterial infections. Methods In 2007, the National Blood Authority first published Criteria for the clinical use of intravenous immunoglobulin in Australia. The Australian Red Cross Lifeblood assessed, approved, and recorded all supply with patient demographics, distribution data, intravenous Ig (IVIg) volumes and treatment episodes. IVIg was the sole product used in Australia from 2008-2013 inclusive. Results From 2008-2013 across Australia, 2,734 individual CLL patients received 48,870 treatment episodes using a total 1,324,926 grams of IVIg therapy. Six IVIg products were available, with domestically manufactured Intragam P accounting for 89.7% of supply. The average age for first dose was 74 years. Males received 60.6% of the total treatment episodes representing 20% more than females. The average pre-treatment IgG level was 4.03g/L +/- 2.03g/L (range 0.30-10.50g/L). A sustained average annual increased IVIg utilisation of 5.5% was observed. There was significant regional variation consistent with differences in prescriber preferences across states and territories. Conclusion This study provides a globally unique insight into IgRT supply and demand in CLL patients by analysis of total national use in Australia over a six year period.

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N-Acetyl-β-D-Glucosaminidase Enzymuria in Leukaemia and Myelomatosis: Effect of Treatment in Acute Myeloblastic Leukaemia and Myelomatosis in Adults

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456328602300609 ◽

1986 ◽

Vol 23 (6) ◽

pp. 676-680 ◽

Cited By ~ 1

Author(s):

P H Whiting ◽

D J King ◽

A Ireland ◽

M A Ratcliffe ◽

A A Dawson

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

Lymphocytic Leukaemia ◽

Normal Values ◽

Terminal Phase ◽

Acute Myeloblastic Leukaemia ◽

Lysosomal Hydrolase ◽

Patient Groups ◽

Effect Of Treatment ◽

Pre Treatment ◽

Serum And Urine

The activity of the lysosomal hydrolase N-acetyl-β-d-glucosaminidase (NAG) was measured in the urine of patients with leukaemia or myeloma. Elevated pre-treatment enzymuria was noted in all patient groups with acute myeloblastic leukaemias (AML) FAB type M4 or 5 displaying higher activities than AML patients FAB types M1–3, which in turn were higher than those found in patients with myelomatosis and chronic lymphocytic leukaemia. The ratio of the major isoenzymes of NAG, A/B was reduced significantly only in patients with AML. Following treatment, AML patients who entered remission demonstrated NAG levels which approached normal values. In those AML patients who were either in relapse, in the terminal phase of their illness or treated with aminoglycoside antibiotics, NAG enzymuria was similar to pre-treatment values. A reduction in urinary NAG levels and both serum and urine β2 microglobulin concentrations was also observed following treatment in myeloma patients. The use of enzymuria both as a guide to progress towards remission in AML patients and for assessing prognosis and progress in myeloma patients is discussed.

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Importance of cellular immunity link for efficiency of replacement therapy in common variable immune deficiency

Medical Immunology (Russia) ◽

10.15789/1563-0625-ioc-1989 ◽

2020 ◽

Vol 22 (4) ◽

pp. 799-804

Author(s):

L. P. Sizyakina ◽

I. I. Andreeva ◽

D. I. Danilova

Keyword(s):

Immune Response ◽

Replacement Therapy ◽

Cellular Immunity ◽

Bacterial Infections ◽

Immune Cell ◽

Respiratory Infections ◽

Combined Treatment ◽

Ivig Therapy ◽

Continuous Treatment ◽

Cellular Immune

Lifetime use of IgG replacement therapy is the standard of CVID treatment. However, full control over stabilization of chronic infection loci is not always achieved, even if this therapy is continuously applied. The purpose of this study was to carry out comparative analysis of changes in cellular component of adaptive and innate immune response, depending on effectiveness of replacement therapy of patients with infectious CVID phenotype. The observation group consisted of 15 patients with CVID who were diagnosed since early childhood in 100% of cases. They had prolonged respiratory infections followed by the development of complications requiring continuous treatment with antibiotics.After reaching mean age of 15 years old, the intensity of infection-associated antibody deficiency was 6-8 times per year. After verification of the diagnosis, the patients received replacement therapy, first at the saturation dose, and, after stabilization of IgG at the level of 7-8 g/l, at the monthly maintenance dose. The clinical course of the disease was traced during a full year of replacement therapy, and the cellular immunity indices were evaluated. In all patients, after a year of therapy corresponding to clinical guidelines, there was an improvement in quality of life indices, decreased rates of recurrent bacterial infections. At the same time, 40% of them continued to suffer, on average, 5.4±1.1 times a year and required long-term courses of antibiotic therapy. Evaluation of immune status did not reveal statistically significant differences in IgG plasma saturation between the groups of patients with different treatment efficiency: 8.7 (8-9) g/l and 9.1 (8.5-10.5) g/l, at p = 0.5. The differences related to immune cell factors in cases of smaller effect of IVIG therapy are manifested in higher relative numbers of T effectors containing lytic Granzyme B granules and CD14+CD284+ monocytes, accompanied by lower spontaneous active oxygen forms produced by neutrophils, lesser contents of CD16+ natural killers in peripheral blood.The obtained data illustrate the value of monitoring, not only serum IgG level, but also the parameters of the cellular immune response. Such analysis may be essential as a prognostic criterion for efficacy of IVIG therapy. Reduced levels of some parameters of innate immunity cells serves a basis to formulate the concept of combined treatment and usage of tools that alter functions of immunocompetent cells.

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Functional abnormalities in granulocytes predict susceptibility to bacterial infections in chronic lymphocytic leukaemia

European Journal Of Haematology ◽

10.1111/j.1600-0609.1996.tb00489.x ◽

2009 ◽

Vol 57 (1) ◽

pp. 46-53 ◽

Cited By ~ 25

Author(s):

M. Itälä ◽

O. Vainio ◽

K. Remes

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

Bacterial Infections ◽

Lymphocytic Leukaemia

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058 ANTI-CASPR2-ANTIBODY associated encephalitis in a 63-year old male with chronic lymphocytic leukaemia

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-anzan.57 ◽

2018 ◽

Vol 89 (6) ◽

pp. A24.1-A24

Author(s):

Kate Lilley ◽

Andrew Swayne ◽

Emily Watson ◽

Rachel Kee ◽

David Wong ◽

...

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

Lymphocytic Leukaemia ◽

Limbic Encephalitis ◽

Case Reports ◽

Clinical Status ◽

Inpatient Rehabilitation ◽

Ivig Therapy ◽

Sleep Apnoea ◽

List Type ◽

Paraneoplastic Limbic Encephalitis

IntroductionThis case from a tertiary neurology centre reports a novel association between the emerging clinical entity of anti-contactin associated protein-2 (CASPR-2) antibody encephalitis and chronic lymphocytic leukaemia (CLL).CaseWe describe a 63 year old Maori male truck-driver who presented with progressive altered personality, speech, cognition and perception over 9 months. The patient also developed choreiform movements, broad-based gait, incontinence, sleep apnoea with type 2 respiratory failure and episodic loss of consciousness. 12 months prior, he had been diagnosed with low-risk CLL, for which he remained untreated. MRI of the brain revealed mid-sagittal bilateral mid-temporal T2/FLAIR hyperintensities. Cerebrospinal fluid examination showed a mononuclear pleocytosis (WCC 270×10^6/L) with 15% of these CD5/CD19/CD23 positive and 92% CD3/CD5 positive CD 19 negative on flow cytometry, protein was also elevated at 2600 mg/L. The interplay between CLL and inflammation is uncertain. Anti-Caspr2-antibody was identified in CSF and serum. The patient was treated with a combination of fludarabine, cyclophosphamide, rituximab, dexamethasone and intravenous immunoglobulin (IVIG). Clinical status improved and antibody titre decreased from 580 to 241 pM in three weeks and to 55pM (negative <85 pM) at five months. Symptoms worsened when IVIG doses were missed. He returned home after inpatient rehabilitation, showed striking clinical improvement at 12 month follow-up and continues on maintenance IVIG therapy.ConclusionWhilst paraneoplastic VGKC encephalitis has been described associated with a number of malignancies, this is the first reported case of CASPR-2 antibody present in association with CLL.References. Van Sonderen A, Petit-Pedrol M, Dalmau J, Titulaer MJ. The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nature Reviews Neurology2017;13(5):290–301.. Nogai H, Israel-Willner H, Zschenderlein R, Pezzutto A. Improvement in Paraneoplastic Limbic Encephalitis after Systemic Treatment with Rituximab in a Patient with B-Cell Chronic Lymphocytic Leukaemia. Case Reports in Haematology2013;2013:Article ID958704.. Van Sonderen A, Ariño H, Petit-Pedrol M, et al. The Clinical Spectrum of Caspr2 antibody-associated disease. Neurology2016;87:521–528.. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, et al. Paraneoplastic limbic encephalitis: Neurological symptoms, immunological findings and tumour association in 50 patients. Brain2000;123:1481–1494.

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SAMHD1, A Putative Tumour Suppressor, Is Recurrently Mutated in Chronic Lymphocytic Leukaemia, and Is Associated with Poor Risk Features

Blood ◽

10.1182/blood.v120.21.713.713 ◽

2012 ◽

Vol 120 (21) ◽

pp. 713-713

Author(s):

Ruth Clifford ◽

Sam Ackroyd ◽

Adam Burns ◽

Adele Timbs ◽

Jonathan Maelfait ◽

...

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukaemia ◽

B Cell ◽

Reverse Transcription ◽

Somatic Mutations ◽

Lymphocytic Leukaemia ◽

Restriction Factor ◽

Whole Genome ◽

Founder Mutations ◽

Pre Treatment

Abstract Abstract 713 Chronic lymphocytic leukaemia (CLL) has a highly variable clinical course. Recent whole genome sequencing (WGS) data reflects this heterogeneity revealing low level recurrent somatic mutations (Puente Nature 2011, Quesada Nat Gen 2011, Wang NEJM 2011, Schuh Blood 2012). Our WGS study of sequential samples from 3 patients revealed candidate founder mutations that were present in all cells at all time-points. We focus on one of the genes affected by founder mutations; SAMHD1. SAMHD1 has been identified as an anti-viral restriction factor that targets HIV-1 by blocking reverse transcription of viral RNA (Laguette Nature 2011, Hrecka Nature 2011). The recently elucidated triphosphohydrolase activity of SAMHD1 leads to depletion of deoxynucleotide triphosphates (dNTP) during reverse transcription, thus interrupting the viral replication cycle before integration into the genome (Goldstone Nature 2011). In constitutional disease, recessive mutations in SAMHD1 have been implicated in deregulation of the innate immune response and development of a congenital autoimmune encephalopathy, Aicardi–Gouti ères syndrome (AGS) (Crow Hum Mol Gen 2009). In our single institutional cohort of 100 1st line and relapsed CLL patients we identified 8 patients with acquired mutations in SAMHD1, of which 6 were chemorefractory (Table 1). This is much higher than the expected frequency of 25% chemorefractory patients in this cohort (Knight Leukemia 2012), implying a correlation between SAMHD1 mutations and poor outcome. In order to precisely establish the incidence of SAMHD1 mutations in patients requiring 1st line treatment, we sequenced 200 samples from patients recruited into first line UK clinical trials. We determined a mutation frequency of 3% (Table 1). Whole genome SNP arrays on our SAMHD1 mutated patients reveals monoalleleic deletions or copy neutral loss of heterozygosity at the SAMHD1 locus in 14 of 15 samples. TABLE 1: SAMHD1 mutated patients Sample Age IgHV mutation TP53 disruption Clinical Status Mutation 1 72 U Neg Pre Treatment c.-166G>T 2 72 M Neg Refractory M1K K523X 3 NK U Neg Refractory Y155C 4 65 U Neg Refractory R145X 5 NK NK NK Pre Treatment R145Q 6 63 U Neg Pre Treatment I136T 7 77 M Neg Refractory E355K 8 68 U Neg Refractory L431S 9 72 U Neg Refractory F545L 10 NK NK NK Pre Treatment W572X 11 69 NK NK Pre Treatment N/A 12 66 M Pos Refractory T365P 13 NK NK Neg Pre Treatment R371H 14 77 M Neg Refractory N/A 15 25 NK Neg AGS N/A U=Unmutated, M=Mutated. Next, we questioned whether patients with congenital SAMHD1 mutations are more susceptible to developing B-cell malignancies. We reviewed 20 patients with AGS and homozygous SAMHD1 mutations. Intriguingly, 2 of these patients have developed a B-cell malignancy. One of these patients presented at 1 month of age with features typical of AGS and has been subsequently diagnosed with CLL at the age of 25. Sequencing the SAMHD1 locus of both germline and CLL cells from this patient confirmed the homozygous 1609-1G4C mutation. We screened the patient's CLL cells for acquired mutations recently found to be recurrent in CLL. None of these genes were mutated suggesting the SAMHD1 germline mutation was sufficient to cause CLL. In addition, whole exome analysis is in progress for a more complete view of acquired mutations potentially contributing to CLL pathogenesis. To evaluate the interplay of recurrent somatic mutations in CLL in the context of our SAMHD1 mutations, we used a custom designed targeted sequencing panel (TruSeq Custom Amplicon, Illumina). SAMHD1 mutations were found exclusively in SF3B1 negative patients. Only one SAMHD1 patient had a TP53 mutation. To begin to functionally define the role of SAMHD1 mutations in CLL, we examined the impact of SAMHD1 mutations on SAMHD1 mRNA gene expression by quantitative PCR analysis of purified CLL cells and normal B cell controls. Expression in the mutated CLL cells was significantly lower compared to normal B cells. From this, we hypothesise that CLL cells with SAMHD1 mutations might show an increase in intracellular dNTP levels. We are currently evaluating the levels of dNTPs using a custom designed qPCR to measure dNTP incorporation onto template DNA. In conclusion, we provide the first evidence that the lentiviral restriction factor and dNTP triphosphohydrolase SAMHD1 acts as a tumour suppressor in human B cells. We propose that deregulation of the dNTP pool in B cells caused by mutations in SAMHD1 might contribute to lymphomagenesis. Disclosures: Ross: Illumina: Employment. Bentley:Illumina: Employment. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Chronic Lymphocytic Leukaemia Drives the Production of T Regulatory Cells From the CD4+ CD25- Compartment with a CD27high/CD127 Low Phenotype.

Blood ◽

10.1182/blood.v114.22.2330.2330 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2330-2330

Author(s):

Karen Piper ◽

Mamtha Karanth ◽

Andrew McLarnon ◽

Emma Kalk ◽

Naeem Khan ◽

...

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

T Regulatory Cells ◽

Lymphocytic Leukaemia ◽

Conflicts Of Interest ◽

Fold Increase ◽

Foxp3 Expression ◽

Regulatory Cells ◽

Pre Treatment ◽

Cellular And Humoral Immunity ◽

And Function

Abstract Abstract 2330 Poster Board II-307 Patients with chronic lymphocytic leukaemia (CLL) have defects in both cellular and humoral immunity including changes in the numbers and function of T regulatory cells (Tregs). The identification of Tregs is an ever-evolving field and in this study we readdressed the phenotype using the markers CD25, FoxP3 and CD127-/lo and confirmed function by classical suppressor assays in CLL patients on and off treatment. Using the combination CD4 and FoxP3 we observed increased Treg frequencies in CLL patients, in particular with advanced disease, supporting previous studies showing an increase in Tregs in CLL. However in contrast to previous studies, there was no increase in the CD25+ FoxP3+ population in CLL patients rather the increase in FoxP3 expression occurred in the CD25- compartment of CLL patients. Interestingly CLL induced a 7-fold increase in the expression of FoxP3 in CD4+CD25- T cells following short-term co-culture. The T regulatory cells in CLL patients had a significantly higher expression of CD27 compared to healthy controls and although CD127 expression was low in both healthy and CLL patients it was significantly lower in CLL patients. Fludarabine treatment initially induced increased expression of FoxP3 in the CD4+ T cell compartment but this declined gradually to reach levels below that pre-treatment. Here we propose that CLL drives the production of Tregs from the CD4+CD25- compartment as has been shown recently in Non-Hodgkins Lymphoma (NHL) and the mechanism of induction could provide alternative avenues for treatment. Disclosures: No relevant conflicts of interest to declare.

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