John Quinn

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.

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

Myeloma presenting during pregnancy

Multiple myeloma predominantly affects the elderly with only 2% of cases presenting under the age of 40 years [1]. Therefore, myeloma presenting in pregnancy is rare with just 16 cases reported [1–4], of which only four received anti-myeloma therapy during pregnancy [1–3]. Because of the rarity of this condition, there are no published recommendations for management, nor is it known if pregnancy has any prognostic relevance. We describe three cases of myeloma presenting in pregnancy. One has previously been reported [5] and we are updating the outcome. In doing so, we suggest a practical approach to treating myeloma presenting during pregnancy that optimizes outcomes for both the mother and baby.

Warfarin and topical miconazole: the potential for a clinically significant interaction

Moran et al. [1] recently surveyed 181 patients who were receiving warfarin therapy with regard to their knowledge of the potential drug interactions, adverse effects and immediate actions in the event of haemorrhage during warfarin treatment. We were particularly interested to note that almost 47.9 % of patients surveyed were unaware of potential interactions between warfarin and other medications and that only 31.8 % of patients were aware that antibiotics could interact with warfarin. These results highlight our recent experience with four patients who were taking concomitant topical miconazole and warfarin, all of whom developed dramatically elevated INR levels. Miconazole is an imidazole anti-fungal medication with actions against a broad variety of fungal species and is widely available in pharmacies as an oral gel without prescription [2]. Although clinically significant interactions between topical miconazole and warfarin have previously been reported, we believe that this potential interaction is not widely recognised by clinicians, pharmacists and patients [3]. Warfarin is mainly metabolised via cytochrome P-450 hepatic microsomal enzyme CYP2C9, and thus drugs that inhibit the actions of this enzyme may lead to supratherapeutic INR levels in patients taking warfarin. Importantly, miconazole, even in its topical form, is known to be a highly potent inhibitor of this enzyme [4–6]. The four cases described below were all attending the oral anticoagulation clinic (OAC) at Beaumont Hospital which has approximately 2,400 patients under review at the present time. Importantly, all the four patients had stable INRs prior to taking topical miconazole (patient details are summarised in Table 1). Amongst the four cases, the indications for warfarin were atrial fibrillation (AF, n = 2), venous thromboembolism (VTE, n = 1) and arterial thromboembolism (ATE, n = 1) with a target INR of 2.5 in all cases. The duration of combined warfarin and topical miconazole ranged from 3 to 7 days and in only one case was accompanied by other new medications (Chlarithromycin, and mycostatin, case four, Table 1). Despite INR values that were broadly within range before commencing miconazole, the INR levels increased rapidly in all the four cases, reaching levels of [10 in 3/4 cases. Minor bleeding (haematuria, case four) complicated one case, but resolved with intravenous vitamin K. Two of the other patients received oral vitamin K and there were no other bleeding complications. Our case series is characterised by the dramatic and rapid increase in INR values following the commencement of miconazole, a feature which has been highlighted in a number of publications to date. In 2002, Devaraj reported the case of an 80-year-old man whose INR rose to 21.4 following concomitant warfarin and topical miconazole treatment [7]. More recently, Kovac et al. [8] reported on 32 warfarinised patients who also received miconazole oral gel. Bleeding occurred in 15/32 patients (7 minor, 8 major), and in keeping with our experience the mean INR increased from 2.44 to 8.8 with concomitant warfarin and miconazole. We believe this interaction to be particularly important because miconazole gel can be purchased in pharmacies without prescription, highlighting the importance of educating patients, their carers and all health care C. C. Ufondu (&) P. Ferrins J. Quinn Departments of Haematology, Beaumont Hospital, Dublin 9, Beaumont, Ireland e-mail: ufondunonso@yahoo.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

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.

Emergence of Bruton's Tyrosine Kinase-negative Hodgkin Lymphoma During Ibrutinib Treatment of Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) is a chronic B‐cell lympho‐proliferative disorder in which lymphomatous transformations occur in 5%‐15% of patients. Histologically these cases resemble diffuse large B‐cell lymphoma, or Richters transformation, in over 80% of cases. Rare cases of transformation to Hodgkin lymphoma (HL) have been reported in the literature with an estimated prevalence of 0.4%. We report a case of a 67‐year‐old female with CLL treated with the novel Brutons tyrosine kinase (Btk) inhibitor, ibrutinib, who subsequently presented with intractable fevers. Bone marrow trephine, and lymph node biopsy revealed classical HL with negative immuno‐histochemistry for Btk in HL cells, on a backdrop of CLL. The patient commenced treatment with Adriamycin, Vinblastine and Dacarbazine (AVD), which resulted in an excellent response. Hodgkin transformation of CLL is rare with a single retrospective study of 4121 CLL patients reporting only 18 cases. Btk expression in HL cells is recently recognised in classical HL; however, the majority of HLs are Btk negative. Given that Btk inhibitors have recently been shown to induce genomic instability in B cells, in the context of their widespread use, such emerging cases are increasingly relevant.

Targeted next-generation sequencing identifies clinically relevant mutations in patients with chronic neutrophilic leukemia at diagnosis and blast crisis

PurposeChronic neutrophilic leukemia is a rare form of myeloproliferative neoplasm characterized by mature neutrophil hyperleukocytosis. The majority of patients harbor somatic mutations of CSF3R gene and are potentially amenable to targeted therapy with JAK inhibitors. The incidence and clinical significance of additional mutations requires clarification.Materials and methodsA next-generation sequencing approach for myeloid malignancy-associated mutations was applied to diagnostic and matched blast crisis samples from four chronic neutrophilic leukemia patients.ResultsNext-generation sequencing confirmed the CSF3R T618I in all patients with identification of concurrent SRSF2, SETBP1, NRAS and CBL mutations at diagnosis. At blast crisis, clonal evolution was evidenced by an increased CSF3R T618I allele frequency and by loss or acquisition of CBL and NRAS mutations.ConclusionThe diagnostic utility of a targeted next-generation sequencing approach was clearly demonstrated with the identification of additional mutations providing the potential for therapeutic stratification of chronic neutrophilic leukemia patients.

A 5-day: the favourable way?

Dear editor, We read with interest the article by Pierdomenico et al. [1] reviewing the efficacy and tolerability of a 5-day doseintensified regimen of azacitidine (100 mg/m/day×5 days) in intermediate-2 and high-risk myelodysplastic syndromes (MDS). While the approved regimen is 75 mg/m/day for 7 days every 28 days [2], a 5-day regimen with the elimination of weekend dosing would be more easily delivered, costeffective and conducive to patient convenience. The clinical concern relates to the administration of a potentially suboptimal dose and its subsequent impact on response and overall survival. To date, no large-scale study, including Lyons et al. [3], have demonstrated the superiority of a 7-day over a 5-day regimen. We retrospectively collected data on 32 MDS patients (treatment naïve) who received a 5-day regimen of azacitidine (75 mg/m/day×5 days, n=27; 100 mg/m/ day×5 days n=5) in four Irish institutions (2006– 2012).The dose regimen was dependent on the preference of each centre. Patients were identified through the Irish MDS registry and were risk-stratified according to the WHO Prognostic Scoring System [4]. No inclusion or exclusion criteria were applied. Median age was 73 years (range 36–89 years) with a male predominance (72 %). MDS subtypes included RAEB-2 (n=15), RAEB-1 (n=4), CMML (n=8), RCMD (n=1), RCMDRS (n=1), RA (n=1), RARS (n=1) and MDS/MPD (n=1). The majority (79 %) had high or very high risk disease. Twenty-three (72 %) were transfusion dependent. Cytogenetic data was available in 84 % (26 % with poor karyotype). Patients received a median of 9 cycles (range 2–32). The modified International Working Group criteria (2006) were used to determine response [5] (Table 1). Survival times (Kaplan–Meier estimates) were calculated from the date of initiation of therapy to the date of death or last follow-up. The overall response rate (ORR)was 47%. Three (9%) achieved a complete remission (with persistent marrow dysplasia) and 12 (38 %), a haematological improvement (HI). The median number of cycles of best response was 4 (range 1–21) with a median duration of 5.5 months. Nine (39 %) became transfusion independent after a mean of 5 cycles (range 1–12 cycles) for a mean duration of 7 months (range 2–16months).Median survival was 20 months (range 3–39 months). Seven patients transformed to AML during follow-up. This was a small multicentre retrospective study of a heterogeneous MDS population. However, ORR was comparable with that of the approved regimen [6], albeit the lower complete response (CR) rate. It is arguable, however, whether a CR is a prerequisite for prolongation of survival [7]. The median survival in this cohort was 20 months which is 4 months short of the AZA001 trial [6] but similar to the results of a 5-day-doseintensified regimen [1]. Randomised studies are necessary to address the issue of whether a 5-day regimen (total monthly dose of 375 or 500 mg/m) is nonC. McHale :N. O’Connell : J. McHugh : P. Evans :H. Enright Department of Haematology, Adelaide and Meath Hospital Incorporating the National Children’s Hospital, Dublin 24, Ireland