Philip T. Murphy

Plasmablastic lymphoma presenting as a paravertebral mass in a patient with Crohn's disease after immunosuppressive therapy.

The case of a 32-year-old man with a paravertebral mass and skin nodules, occurring against a background of immunosuppressive therapy for Crohn’s disease, is presented. The tumours showed morphological and immunophenotypical features of plasmablastic lymphoma. To our knowledge, this is the first reported case of plasmablastic lymphoma presenting in this location, and also after immunosuppression with infliximab treatment for Crohn’s disease.

A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia.

This retrospective analysis assessed the response, safety and duration of response to standard dose rituximab 375 mg/m2 weekly for four weeks as therapy for patients with primary or secondary warm autoimmune haemolytic anaemia (WAIHA), who had failed initial treatment. Thirty‐four patients received rituximab for WAIHA in seven centres in the Republic of Ireland. The overall response rate was 70·6% (24/34) with 26·5% (9/34) achieving a complete response (CR). The time to response was 1 month post‐initiation of rituximab in 87·5% (21/24) and 3 months in 12·5% (3/24) of patients. The median duration of follow‐up was 36 months (range 6–90 months). Of the patients who responded, 50% (12/24) relapsed during follow up with a median time to next treatment of 16·5 months (range 6–60 months). Three patients were re‐treated with rituximab 375 mg/m2 weekly for four weeks at relapse and responded. There was a single episode of neutropenic sepsis. Rituximab is an effective and safe treatment for WAIHA but a significant number of patients will relapse in the first two years post treatment. Re‐treatment was effective in a small number of patients, suggesting that intermittent pulse treatment or maintenance treatment may improve long‐term response.

Bortezomib-induced reversible posterior leucoencephalopathy syndrome.

A 66-year-old man presented midway through his third cycle of bortezomib treatment for refractory Waldenström macroglobulinaemia with new onset generalized tonic–clonic seizures and altered mental status. He was moderately hypertensive and neurological examination was unremarkable. Plasma viscosity, blood glucose and electrolytes were within normal limits. Magnetic resonance imaging (MRI) of brain showed extensive asymmetrical high signal in the subcortical white matter of the occipital lobes, consistent with posterior leucoencephalopathy (figure). Major intracranial vessels were patent. A diagnosis of posterior leucoencephalopathy secondary to bortezomib therapy was made. Treatment with bortezomib was discontinued and antihypertensives were started. No further seizures occurred and repeat MRI imaging 3 months later was normal. Reversible posterior leucoencephalopathy is characterised by reversible clinical features including seizures, headaches, altered mental state and visual loss. Typically, an MRI shows subcortical oedema without infarction in both posterior cerebral hemispheres. Common causes include immunosuppressants, chemotherapy and hypertensive encephalopathy. Treatment involves prompt recognition, withdrawal of the offending agent and management of hypertension. Bortezomib is increasingly being used as a highly effective agent to treat plasma cell disorders. We recommend prompt MRI in patients on bortezomib with the above clinical findings.

Urinary hepcidin excretion in patients with low grade myelodysplastic syndrome

The recent correspondence by Winder et al (2008) provided, for the first time, data on urinary hepcidin excretion in patients with various forms of myelodysplastic syndrome (MDS), suggesting that urinary hepcidin levels are inappropriately low relative to serum ferritin and thus contribute to the iron overload that is often observed in these disorders. We have previously noted functional iron deficiency, as measured by raised percentage hypochromic red cells (PHC) and red cell zinc protoporphyrin (ZnPP) levels, in some patients with low grade MDS [refractory anemia (RA), refractory cytopenia with multilineage dysplasia (RCMD), refractory anemia with ring sideroblasts (RARS) and refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS)] (Murphy et al, 2006), and hypothesised that such functional iron deficiency might contribute to suppression of hepcidin production in these disorders. Following ethical approval and informed signed patient consent, we measured urinary hepcidin levels by mass spectrometry (Kemna et al, 2007) in 17 consecutive patients with low grade MDS (1 RA, 11 RCMD, 1 RARS, 4 RCMD-RS) and correlated the results with complete blood count, including PHC (normal <5%) (measured on the Bayer ADVIA 120 automated blood counter analyser), as well as serum ferritin, percentage transferrin saturation and ZnPP (normal range 0– 3 lg/g Hb). We also calculated urinary hepcidin/serum ferritin ratios as a measure of the appropriateness of urinary hepcidin

Progressive multifocal leukencephalopathy and cerebral toxoplasmosis in a patient with CLL.

A 63-year-old man with a 10 year history of Chronic Lymphocytic Leukemia (CLL) presented with apraxia, forgetfulness, and cognitive impairment. He had been treated with single agent fludarabine at diagnosis and combination therapy with fludarabine, cyclophosphamide, and rituximab 8 months previously. MRI showed high signal in the white matter of right frontal, left frontal, and parietal areas. (see Image 1) Cerebrospinal fluid (CSF) analysis was normal with no organisms seen. Brain biopsy showed white matter replacement with oligodendroglial intranuclear inclusions and adjacent ruptured toxoplasmosis cysts. (see Image 2) Immunohistochemistry was positive for JC virus and PCR of CSF confirmed the presence of the virus as well as toxoplasma. He developed progressive ataxia, dysphagia, and dementia and died 4 weeks after diagnosis. Progressive multifocal leukoencephalopathy is associated with the use of purine analogues and rituximab in CLL [1,2]. The incidental finding of toxoplasma illustrates how markedly immunosuppressive these regimens are.

Dialysis-dependent renal failure at diagnosis continues to be associated with very poor outcome in multiple myeloma.

Chang, W.J., Kim, S.J. & Kim, K. (2014) Central nervous system myeloma : a different cytogenetic profile? British Journal of Haematology, 164, 745–748. Gozzetti, A., Cerase, A., Lotti, F., Rossi, D., Palumbo, A., Petrucci, M.T., Patriarca, F., Nozzoli, C., Cavo, M., Offidani, M., Floridia, M., Berretta, S., Vallone, R., Musto, P., Lauria, F. & GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) Myeloma Working Party (2012) Extramedullary intracranial localizations of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients. Cancer, 118, 1574–1584.

Co-existing chronic myeloid leukaemia and multiple myeloma: rapid response to lenalidomide during imatinib treatment

We read with particular interest the recent case report by Ide et al. [1] and others [2–5] describing the rare occurrence of a patient with co-existent chronic myeloid leukaemia (CML) and multiple myeloma (MM). Here, we describe a further case in which CML and MM presented simultaneously, and in which commencement of imatinib was followed shortly by MM disease progression. A 71-year-old woman was referred to our department in August 2003 with leucocytosis, anaemia and thrombocytosis. She was asymptomatic and physical examination was unremarkable. Complete blood count (CBC) showed: haemoglobin (Hb) 9.3 g/dL, platelets 564 9 10/L, white cell count (WCC) 12.7 9 10/L with neutrophils 10 9 10/L. Bone marrow aspirate was hypercellular, and showed granulocytic hyperplasia without an increase in blasts. Furthermore, there was an infiltrate of atypical plasma cells accounting for 30% of nucleated cells. Serum protein electrophoresis showed an IgG kappa paraprotein band of 42 g/L with immune paresis. Renal function and serum calcium were normal, and serum b-2-microglobulin was elevated at 5.0 mg/L. Skeletal survey did not show any lytic bone disease. Anti-myeloma treatment was initially deferred, whilst other causes for anaemia were sought. Six months later, the patient’s WCC had risen to 37.2 9 10/L and cytogenetic analysis of a repeat bone marrow aspirate showed 46XX, t(9;22)(q34;q11) in all cell metaphases, confirming a diagnosis of CML. Treatment with imatinib 400 mg once daily was commenced and the patient responded rapidly, achieving a complete molecular remission after 9 months of treatment (measured by reverse transcriptase nested PCR sensitive to 1/10,000 dilution). However after 6-month treatment with imatinib, the patient’s IgG paraprotein had risen to 57.6 g/Lin keeping with MM disease progression. The patient received five cycles of melphalan and prednisolone, resulting in a marginal drop in serum paraprotein to 49.4 g/L. Thereafter, she received five complete cycles of bortezomib (1.3 mg/m) and dexamethasone, which was complicated by grade I peripheral neuropathy without any significant reduction in serum paraprotein, with a repeat bone marrow aspirate showing 60% plasma cells (see Fig. 1 for MM disease course). Thereafter, alternate day oral cyclophosphamide therapy resulted in frequent interruptions in treatment because of neutropenia without reduction in serum paraprotein level. At this point with the serum paraprotein at 50.8 g/L, lenalidomide and dexamethasone treatment was commenced, and the serum paraprotein fell to 9.1 g/L within 3 months (Fig. 1). Lenalidomide was commenced at a dose of 25 mg daily (21 from 28 days) for the first four cycles; however, significant neutropenia led to a dose reduction to 15 mg daily for cycle 5 and further to 5 mg daily from cycle 6 onwards. In addition, G-CSF was administered intermittently to maintain a neutrophil count [1.0 9 10/L but significant thrombocytopenia was not encountered. After 17 months of lenalidomide treatment, the dose was further reduced to 5 mg alternate days, on which she remains. Importantly, imatinib was continued throughout treatment with both lenalidomide and bortezomib, and the patient has maintained a complete molecular response to the present day. Our case is important for a number of reasons. Firstly, we believe this to be the first patient with both CML and MM who has been treated with both bortezomib and lenalidomide in combination with imatinib. Although her condition was bortezomib-refractory, the patient showed C. Offiah (&) J. P. Quinn P. Thornton P. T. Murphy Department of Haematology, Beaumont Hospital, Dublin 9, Ireland e-mail: chikaoffiah@gmail.com

A case of leptospirosis presenting as TTP.

Immunomodulatory drugs (IMiDs), thalidomide and its derivative lenalidomide, have emerged as an effective treatment for relapsed/refractory multiple myeloma (MM). Clinical studies have demonstrated that thalidomide and lenalidomide each have their own distinct toxicity and efficacy [1–4] despite sharing an overlapping immunomodulatory profile [5,6]. It is evident that patients previously refractory to the less potent IMiD thalidomide can still respond when treated with lenalidomide [7,8]. However, the efficacy of thalidomide in patients refractory to lenalidomide is largely unknown. Two recent studies have looked at the use of thalidomide as a possible treatment regimen post-lenalidomide. Firstly, Guglielmelli et al. [9] followed a diverse group of 20 patients with MM that relapsed while on a reduced maintenance dosage of lenalidomide and treated these patients with a thalidomide-based salvage regimen. Their results showed a 10% overall response of equal or greater than partial response ( PR) and median response duration of 5 months. Secondly, Madan et al. [10] reported an overall response rate of 25% in a subset of four patients with lenalidomide refractory MM subsequently treated with thalidomide. We retrospectively studied 24 patients with advanced MM with relapsed disease, refractory disease, or intolerance to full dose lenalidomide and dexamethasone that were subsequently treated with a thalidomide-based regimen. In our study, the median age of subjects at the start of thalidomide therapy was 67 years (44–83) with 67% of patients being males. Monoclonal types were IgG 54% (n 5 13), IgA 33% (n 5 8), and free light chains comprising 13% (n 5 3). Seven patients (29%) had a prior thalidomide exposure pre-lenalidomide either as induction therapy pre-autologous stem cell transplant (ASCT), post-ASCT maintenance or treatment in a relapsed setting. Median time to re-exposure of thalidomide (post lenalidomide) from the end of initial exposure (pre-lenalidomide) for the described seven patients was 2.9 years (1.2–4.0 years). The same seven patients that received thalidomide prior to lenalidomide when compared to the remaining 17 patients exposed to thalidomide only post-lenalidomide had an expectedly reduced median treatment duration and overall response to thalidomide regimen given after lenalidomide (84 versus 103 days; 29 versus 35%). However, these values were not statistically significant. Table I summarizes the lenalidomideand thalidomide-based regimen and responses for all 24 patients. Nineteen of these patients tolerated and eventually progressed on lenalidomide having median treatment duration of 11.1 months, comparable with 11.3 months reported by the MM009 trial [2]. Overall, response to thalidomide-based regimen post-lenalidomide resulted in nine patients (38%) achieving a very good partial response or a partial response (VGPR 1 PR) and 13 patients (54%) achieving less than a partial response, stable disease or progressive disease (SD 1 PD). No complete responses (CR) were observed. Progression-free survival for all 24 lenalidomide-treated patients receiving thalidomide-based treatment was a median of 3.1 months (95% CI; 63–226 days) and overall survival was a median of 9.6 months (95% CI; 255–444 days). In the thalidomide containing responsive group (VGPR 1 PR), the median duration of thalidomide-based treatment was improved to 9.1 months (95% CI: 2.8–19.3) A case of leptospirosis presenting as TTP

Aplastic anaemia preceding acute lymphoblastic leukaemia in an adult with isolated deletion of chromosome 9q

Aplastic anaemia (AA) can precede acute lymphoblastic leukaemia (ALL) in 2% of children but this is rarely reported to occur in adults. A 21-year-old male presented with bone marrow failure and bone marrow biopsy showed a profoundly hypocellular marrow. He recovered spontaneously but represented 2 months later when he was diagnosed with pre-B acute lymphoblastic leukaemia. Chromosomal examination revealed 46,XY,del(9)(q13q34). To the best of our knowledge this is the first case to be reported of aplasia preceding ALL with 9q minus as the sole chromosomal abnormality.

Myelodysplastic patients with raised percentage of hypochromic red cells have evidence of functional iron deficiency

Raised percentage hypochromic red cells (%HRC) were detected at diagnosis in 10 of 34 consecutive patients with low-risk myelodysplastic syndrome (MDS) [refractory anemia (RA) (4/26) and RA with ring sideroblasts (6/8)], all of whom had normal or increased serum ferritin and bone marrow iron stores. Elevated %HRC has persisted in all 10 cases and subsequently developed in another RA patient who later had a complete remission of MDS with normalisation of %HRC after a respiratory tract infection. A strong positive correlation was found between %HRC and erythrocyte zinc protoporphyrin levels in 11 MDS patients tested (p=0.01), suggesting that functional iron deficiency contributes to ineffective erythropoiesis in cases of MDS with raised %HRC. Five of seven patients with elevated %HRC had satisfactory haemoglobin responses to a trial of human recombinant erythropoietin without iron supplementation.