Extreme Thrombocytosis in Refractory ITP Post-Splenectomy With Associated Fatal Thromboembolism.

Thrombopoietin (TPO)-receptor agonists have heralded a paradigm shift in the treatment of refractory immune thrombocytopenia (ITP). Reactive thrombocytosis has been described as a secondary effect of such therapies. However, the phenomenon of extreme thrombocytosis with morphology mimicking a myeloproliferative neoplasm (MPN) followed by fatal thromboembolism is unusual in this setting. Caution is required in the diagnosis of refractory ITP as well as TPO-receptor agonist dosing in such cases.

Large granular lymphocytosis: A novel association with immunotherapy.

Although reactive large granular lymphocytosis due to diverse etiologies is not an uncommon finding in clinical practice, isolated natural killer (NK)-cell lymphocytosis is unusual and its association with immunotherapy has not been described thus far. We provide a brief analysis of a patient with this unique hematological corollary of immunotherapy being increasingly used in the setting of both solid organ and hematological malignancies, and highlight this as an additional differential to consider in the diagnosis of large granular lymphocytosis. Also explored is the importance of recognizing and monitoring the potential hematological manifestations of experimental immunotherapies, as well as the possible implicated mechanisms of action. It is hypothesized that quantification of large granular lymphocytosis may potentially be used as a surrogate marker of therapeutic efficacy in this setting.

Proliferative Glomerulonephritis With Fibrils, Monoclonal κ Light Chain, and C3 Deposits.

There is increasing recognition of monoclonal gammopathy as a cause of proliferative glomerulonephritis (GN), including cases in which glomerular deposition of monoclonal immunoglobulin is demonstrated. Recently, proliferative GN with monoclonal immunoglobulin deposits (PGNMID) has incorporated a light chain variant of the disease (termed PGNMID-LC). Intriguingly, glomerular co-deposition of C3 is found in addition to monotypic light chain, implying complement activation via the alternative pathway (AP). We present a unique case of proliferative GN in a 42-year-old man who presented with nephrotic syndrome and was found to have κ light chain multiple myeloma. Immune staining of the glomerulus was positive only for κ light chain and C3, with the striking appearance of nonamyloid fibrils on electron microscopy. Following clonally targeted therapy for myeloma, the renal clinical abnormalities resolved completely. We present detailed molecular studies for light chain and complement and consider local mechanisms whereby monoclonal κ light chain fibrils may have triggered AP activation within the glomerulus.

A practical guide to laboratory investigations at diagnosis and follow up in Waldenström macroglobulinaemia: recommendations from the Medical and Scientific Advisory Group, Myeloma Australia, the Pathology Sub-committee of the Lymphoma and Related Diseases Registry and the Australasian Association of Clinical Biochemists Monoclonal Gammopathy Working Group.

Waldenström macroglobulinaemia (WM) is an indolent non-Hodgkin lymphoma which usually presents with symptoms related to infiltration of bone marrow or other tissues like lymph nodes, liver or spleen and has certain unusual clinical manifestations, e.g., renal and central nervous system (CNS) involvement. It also has an array of laboratory features including hypersecretion of IgM, cryoglobulinaemia, increased plasma viscosity and identification of mutated MYD88L265P in more than 90% of cases. In this review, we aim to provide a guide to the laboratory investigations recommended for WM at initial diagnosis and at follow-up. A discussion on the nuances of diagnosis and differential diagnoses is followed by bone marrow (BM) assessment, measurement of paraprotein and other ancillary investigations. Recommendations are provided on laboratory work-up at diagnosis, in the asymptomatic follow-up phase, and during and post-treatment. Finally, we briefly discuss the implications of laboratory diagnosis in regard to recruitment and monitoring on clinical trials.

Role of bone marrow biopsy for fever of unknown origin in the contemporary Australian context.

BACKGROUND: Bone marrow biopsy (BMB) is an accepted investigation in fever of unknown origin (FUO) to uncover haematological malignancies, such as lymphoma, and sometimes infections. With the advance in imaging modalities, such as 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) to identify the focus of lymphoma, BMB may not contribute to the diagnosis when there are no other clinical features to suggest an underlying haematological disease. AIM: To investigate the utility of BMB in determining the cause of FUO, when there are no other indications for BMB. METHODS: Medical records of adult patients who had BMB performed for FUO or febrile illness from 1 January 2005 to 31 December 2014 in four metropolitan tertiary hospitals in Melbourne, Australia were reviewed. Patients with other concurrent indications for BMB, known human immunodeficiency virus infection and previously diagnosed connective tissue diseases were excluded. RESULTS: Seventy-three patients were included in the study. Fifty-one patients had a final diagnosis for fever (systemic inflammatory diseases, infective, malignancy or other) while 22 patients had no diagnoses. In only 10 patients (13.7%) did BMB contribute to the diagnosis, finding either malignancy or granulomata. However, all these diagnoses could have been made without BMB. Two patients with diffuse large B-cell lymphoma had normal BMB. FDG-PET was helpful in making a diagnosis in eight (25%) out of 32 patients. CONCLUSION: Performing BMB in patients with FUO and no other haematological abnormalities is of very limited value, and other investigations, such as FDG-PET, may be more likely to help establish a definitive diagnosis.

Intrasinusoidal pattern of bone marrow infiltration by hepatosplenic T-cell lymphoma.

Hepatosplenic T-cell lymphoma is a rare, aggressive form of extranodal lymphoma, which frequently involves the bone marrow. An intrasinusoidal pattern of infiltration is characteristic of the disease and is often best appreciated on immunohistochemical staining. Bone marrow biopsy can be a useful diagnostic tool.

Lifetime alcohol intake and risk of non-Hodgkin lymphoma: Findings from the Melbourne Collaborative Cohort Study.

Cohort studies have reported inconsistent evidence regarding alcohol intake and risk of non-Hodgkin lymphoma (NHL), mostly based on alcohol intake assessed close to study enrolment. We examined this association using alcohol intake measured from age 20 onwards. We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 37,990 participants aged 40-69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between alcohol intake (g/day) and NHL risk. After a mean follow-up of 19.3 years, 538 NHL cases were diagnosed. Approximately 80% of participants were either lifetime abstainers or consumed below 20 g of ethanol/day. All categories of lifetime alcohol intake were associated with about 20% lower incidence of NHL compared with lifetime abstention, but there was no evidence of a trend by amount consumed (HR = 0.97 per 10 g/day increment in intake, 95% CI: 0.92-1.03; p value = 0.3). HRs for beer, wine and spirits were 0.91 (95% CI: 0.83-1.00; p value = 0.05), 1.03 (95% CI: 0.94-1.12; p value = 0.6), and 1.06 (95% CI: 0.83-1.37; p value = 0.6), respectively, per 10 g/day increment in lifetime intake. There were no significant differences in associations between NHL subtypes. In this low-drinking cohort, we did not detect a dose-dependent association between lifetime alcohol intake and NHL risk.

Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax.

The BCL2 inhibitor venetoclax achieves responses in ∼79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials. Investigations at progression included positron emission tomography scan and biopsy. Twenty-five (37%) patients manifested PD on therapy: 17 with Richter transformation (RT) and 8 with progressive CLL/SLL. RT occurred significantly earlier (median 7.9 months) than progressive CLL (median 23.4 months) (P = .003). Among patients who received the recommended phase 2 dose of venetoclax or higher (≥400 mg/d), fludarabine refractoriness and complex karyotype were associated with progression (hazard ratio 7.01 [95% confidence interval 1.7-28.5]; P = .002 and 6.6 [1.5-29.8]; P = .005, respectively), whereas del(17p) and/or TP53 mutation were not (P = .75). Median postprogression survival was 13 (<1-49.9) months. Bruton tyrosine kinase inhibitors were active in progressive CLL, but outcomes were mixed. Patients with disease that is fludarabine refractory or who have complex cytogenetics should have occult RT excluded before initiating venetoclax therapy.

Role of immunohistochemistry in the era of genetic testing in MYC-positive aggressive B-cell lymphomas: a study of 209 cases.

AIMS: MYC rearrangements with or without BCL2 rearrangements have been shown to be associated with poor prognosis and inferior survival in diffuse large B-cell lymphomas (DLBCL). Most of these cases are still diagnosed by fluorescent in situ hybridisation (FISH) testing, which is expensive, requires expertise and is not routinely available in all laboratories. Immunohistochemistry (IHC) is widely available and has the potential to be used as a screening test to identify cases with increased protein expression and select cases that require confirmatory testing. We correlated the expression of MYC and BCL2 by IHC with FISH studies in an attempt to define a cut-off value, which can be used by laboratories to select cases requiring confirmatory FISH testing. The prevalence of MYC-positive DLBCL and double-hit lymphoma (DHL) has also been studied. METHODS: 209 cases comprising of 15 cases of Burkitt lymphoma (BL), 13 cases of intermediate BL/DLBCL and 181 cases of DLBCL were included. IHC and FISH for MYC and BCL2 were performed and the results were correlated. RESULTS: The prevalence of MYC-positive DLBCL and MYC/BCL2DHL was 13.4% and 7.4%, respectively, in our study. Germinal-centre subtype was more common in MYC-positive DLBCL and DHL. MYC-positive DLBCL also showed higher median Ki-67 (>90%) and CD10 positivity as compared with MYC-negative cases. CONCLUSIONS: IHC can be used for screening cases, which require further confirmatory FISH testing. We recommend a cut-off value of ≥30% for MYC by IHC; however, international standardisation of these values is necessary to provide uniformity among laboratories.