Pasquale Fedele

Infusional dose-adjusted epoch plus bortezomib for the treatment of plasmablastic lymphoma

Dear Editor, Plasmablastic lymphoma (PBL) is a rare disease with a poor prognosis with standard chemotherapy. We report an HIV-negative patient with a diagnosis of stage IV PBL successfully treated with bortezomib in combination with infusional dose-adjusted EPOCH (V-EPOCH). A 72-year-old man presented with weight loss of 10 kg over 3 months and progressive lethargy. Performance status was ECOG 0. His medical history includes rheumatoid arthritis, stable on a combination of prednisolone, leflunomide, sulfasalazine, hydroxychloroquine and etanercept. Laboratory testing revealed a mild normocytic anaemia, raised lactate dehydrogenase (LDH) of 302 U/L (100–200), and raised serum kappa free light chains at 349.1 mg/L (3.3– 19.4) with normal lambda light chains and normal serum protein electrophoresis. Serology was positive for EBV IgG and negative for CMV, HIV, hepatitis B and C. PET/CT identified extensive thoracic and abdominal lymphadenopathy; a large left sided pleural effusion and extra-nodal involvement of the spleen, stomach, bone and pleura (Fig 1). CT-guided biopsy was diagnostic for plasmablastic lymphoma with strong positivity for CD138, kappa-ISH and EBV-ISH. The Ki67 proliferative index was 75 %. Fluorescence in situ hybridisation revealed the presence of t(8;14). Bone marrow biopsy was uninvolved. Final disease staging was IVB. Treatment was commenced with dose-adjusted EPOCH [1] in combination with bortezomib 1.3 mg/m2 subcutaneously day 1 and 8 of each cycle. Supportive care included filgrastim 300 mcg, prophylactic valacyclovir and trimethoprim/sulfamethoxazole. The patient received a total of 6 cycles of V-EPOCH and six doses of intrathecal methotrexate (12.5 mg) as CNS prophylaxis. Treatment was well tolerated and he achieved a complete metabolic remission after cycle two (Fig 1). He remains in clinical remission more than 2 years later. The lack of efficacy of CHOP or CHOP-like regimens in PBL has led to the use of more intensive therapies, including infusional DA-EPOCH, following evidence of its efficacy in DLBCL [2]. Bortezomib has well-established efficacy in the treatment of multiple myeloma with emerging evidence of potential efficacy in relapsed/refractory non-germinal centre DLBCL [3]. PBL is typified by the expression of the plasma cell transcription factors Irf4, Blimp1 and Xbp1 [4–6]. Expression of Xbp1 and Blimp1 has been linked with efficacy of bortezomib in myeloma [7, 8], likely due to driving antibody production and hence reliance on the unfolded protein response [9]. In addition, Xbp1 mutations have been shown to lead to disease resistance [8]. The successful use of V-EPOCH has recently been reported in a small case series of two HIV-associated and one non-HIV case of PBL [10]. Our case adds further support to the efficacy of this approach, and demonstrates its tolerability in an older patient. Although the retrospective report of four patients is inadequate for definitive conclusions, the consistency of our experience with that of Castillo and colleagues is encouraging. The reduced frequency of bortezomib dosing (days 1 and 8 * Pasquale L. Fedele pasquale.fedele@monashhealth.org

Profiling clinical platelet and plasma use to inform blood supply and contingency planning: PUPPY, the prospective utilization of platelets and plasma study

Demand for platelet (PLT) and plasma transfusions is increasing. Improved clinical supply and contingency planning requires greater understanding of usage profiles and urgency of clinical requirement.

Anabolic androgenic steroids, an easily forgotten cause of polycythaemia and cerebral infarction

Excessive anabolic androgenic steroids (both exogenous and endogenous) are known causes of polycythaemia and ischaemic cardiovascular events. Despite this, they are commonly forgotten in the workup of patients. We report a case of exogenous anabolic androgenic steroid‐induced polycythaemia and stroke and explore possible pitfalls for clinicians.

Immunochromatographic antigen testing alone is sufficient to identify asymptomatic refugees at risk of severe malaria presenting to a single health service in Victoria

Summary Current screening guidelines for malaria in new refugees include a combination of thick and thin film examination and immunochromatographic antigen test (ICT). However, as the prevalence of malaria in our population has decreased due to changing refugee demographics, we sought to determine if an ICT alone can reliably exclude malaria in our asymptomatic refugee population. A retrospective analysis was conducted of all investigations for malaria performed from 1 August 2011 to 31 July 2013, including thick and thin blood film examination, BinaxNOW ICT, and external morphological and polymerase chain reaction (PCR) validation where applicable. Malaria was diagnosed in 45 of 1248 (3.6%) patients investigated, all of whom were symptomatic and the majority (71.1%) returned travellers. All 599 asymptomatic refugees screened were negative. Overall, 42 of 45 malaria cases were detected by the ICT; sensitivity 93.3% (95% CI 80.7–98.3%) and negative predictive value (NPV) 99.8% (99.2–99.9%). All 21 cases of Plasmodium falciparum and 20 of 22 cases of Plasmodium vivax were detected, giving a sensitivity of 100% (80.8–100%) and 90.9% (69.4–98.4%) respectively. Too few cases of Plasmodium malariae and no cases of Plasmodium ovale or Plasmodium knowlesi were diagnosed for adequate assessment to be carried out. These data suggest that full malaria screening in all asymptomatic refugees with the combination of thick and thin blood films and rapid antigen test may not be warranted. Alternative screening approaches should be considered, including the use of ICT alone, or limiting screening of asymptomatic refugees to only those originating from countries with high incidence of malaria.

DCEP as a bridge to ongoing therapies for advanced relapsed and/or refractory multiple myeloma

Abstract There is limited data describing dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) in relapsed refractory multiple myeloma (RRMM). We reviewed 65 patients with RRMM receiving DCEP between 2005 and 2017 in two Melbourne Hospitals. Patients had received a mean of three prior treatment lines (range, 1–11). The mean number of cycles of DCEP was two (range, 1–4). Overall response rate (ORR) was 55% whilst 19% achieved MR and SD. Median overall survival (OS) was 9.6 months. Those bridged to autologous stem cell transplant (ASCT) had significantly improved OS compared to those who were not (median 32.8 vs. 10.7 months, p=.0004). Significant treatment-related mortality (TRM) was observed (9.7%), mostly attributable to grade 3–4 neutropenia and febrile neutropenia. Mandatory use of G-CSF is, therefore, warranted to prevent septic complications. In heavily pretreated RRMM, DCEP is an effective bridge to definitive therapy but in the absence of the latter, its value is questionable.

Failure to achieve early disease response is associated with inferior survival in patients with newly diagnosed multiple myeloma

adult population; characterization of genetic aberrations by FISH and RT-PCR. Modern Pathology, 23, 866–873. Sovani, V., Harvey, C., Haynes, A.P., McMillan, A.K., Clark, D.M. & O’Connor, S.R. (2014) Bone marrow trephine biopsy involvement by lymphoma: review of histopathological features in 511 specimens and correlation with diagnostic biopsy, aspirate and peripheral blood findings. Journal of Clinical Pathology, 67, 389–395. Suarez, F., Lortholary, O., Hermine, O. & Lecuit, M. (2006) Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood, 107, 3034–3044. Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J. & Vardiman, J.W. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC, Lyon. Taddesse-Heath, L., Pittaluga, S., Sorbara, L., Bussey, M., Raffeld, M. & Jaffe, E.S. (2003) Marginal zone B-cell lymphoma in children and young adults. American Journal of Surgical Pathology, 27, 522–531.

IMiDs through loss of Ikaros and Aiolos primes myeloma cells for daratumumab mediated killing by upregulation of CD38

Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPRCas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC “axis”, as neither protein was consistently downregulated despite cell death occurring and overexpression of either factor failed to rescue for Ikaros loss. Importantly Ikaros and Aiolos repress the expression of interferon stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodelling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab induced NK cell mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs, and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies. For personal use only. on September 19, 2018. by guest www.bloodjournal.org From

Pitfalls of immunotherapy: lessons from a patient with CTLA-4 haploinsufficiency

BackgroundDaclizumab is a humanized monoclonal antibody that blocks CD25, the high affinity alpha subunit of the interleukin-2 receptor. Daclizumab therapy targets T regulatory cell and activated effector T cell proliferation to suppress autoimmune disease activity, in inflammatory conditions like relapsing and remitting multiple sclerosis. Here, we present the first report of agranulocytosis with daclizumab therapy in a patient with relapsing and remitting multiple sclerosis.Case presentationOur patient was a 24-year-old Australian female with a clinical history of atopy, lymphocytic enteritis complicated by B12 deficiency, relapsing and remitting multiple sclerosis, recurrent lower respiratory tract infections, vulval/cervical intraepithelial neoplasia and melanoma. She was commenced on daclizumab therapy after failing several lines of treatment for relapsing and remitting multiple sclerosis. During a hospital admission for lymphocytic enteritis, she was incidentally diagnosed with combined immunodeficiency with hypogammaglobulinaemia and declined proposed regular intravenous immunoglobulin infusions. Following six months of daclizumab therapy, our patient presented to hospital with febrile neutropenia. No clear infective cause was found, despite numerous investigations. However, bone marrow biopsy revealed agranulocytosis with an apparent maturation block at the myeloblasts stage. Neustrophil recovery occurred following cessation of daclizumab and the initiation of T cell immunosuppressive agents including systemic corticosteroids and methotrexate. The patient was further investigated for combined immunodeficiency and whole exome sequencing revealed a novel heterozygous missense variant in cytotoxic T lymphocyte antigen 4 (CTLA4), leading to a diagnosis of CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI).ConclusionThis case demonstrates that autoimmune disease may be the presenting feature of primary immunodeficiency and should be appropriately investigated prior to the commencement of immunotherapy. Genetic clarification of underlying primary immunodeficiency may provide critical clinical information that alters the safety of the proposed treatment strategy.

Acute monocytic leukemia masked by hemolytic anemia and sclerotic lesions

Dear Editor, We report the case of an 80-year-old male who presented with lethargy and shortness of breath. He had a previous history of warm autoimmune hemolytic anemia diagnosed 1 year earlier. His hemolytic anemia was responsive to corticosteroids and therapy had been successfully ceased 6 months prior to presentation. Additionally, the patient had a history of localized prostate cancer managed with androgen deprivation therapy and radiotherapy 6 years earlier and thought to be in remission. Investigations revealed a marked anemia with hemoglobin of 56 g/L but normal white cell count and platelets. Hemolytic indices confirmed warm autoimmune hemolysis with raised lactate dehydrogenase (LDH) of 1195 U/L, raised reticulocyte count (355 × 10/L), raised bilirubin (93umol/L) and undetectable haptoglobin. A blood film revealed marked polychromasia and numerous spherocytes (Fig. 1a). Direct antiglobulin testing confirmed positivity to IgG. He was admitted to hospital, commenced on 1 mg/kg of prednisolone and transfused until symptoms resolved. Due to the recurrence of hemolytic anemia, further investigation was undertaken to exclude potential secondary causes such as an underlying malignancy. Bone marrow aspiration and trephine revealed increased erythropoiesis in keeping with hemolysis; however, no evidence of malignancy was demonstrated, including on subsequent karyotype testing and flow cytometry. A CT scan of the neck, chest, abdomen, and pelvis revealed multiple sclerotic lesions in his spine (Fig. 1b—red arrows). PSA levels remained suppressed at 0.2ug/L. CT-guided biopsy of the sclerotic spinal lesions was unsuccessful, and at patient’s request, he was discharged with ongoing outpatient follow-up. On review as an outpatient 4 days after discharge, his hemoglobin was stable at 97 g/L but his hemolytic indices indicated ongoing hemolysis. A repeat biopsy of his vertebral sclerotic lesions was planned and the patient remained on corticosteroids. Four days after outpatient review, his blood film changed to a leucoerythroblastic picture with 13 % blasts (Fig. 1c). He was readmitted and underwent repeat bone marrow biopsy that revealed a dry aspirate. On bone marrow trephine there was a lack of maturing granulopoiesis with replacement with large immature blasts (Fig. 1d) that expressed CD45, CD4, CD43, CD56, and CD68, consistent with acute monocytic leukemia. Despite commencement of thioguanine, the patient had rapid progression of disease and passed away 5 days after the second bone marrow biopsy. This case highlights the importance of close monitoring of patients with warm autoimmune hemolysis. Warm autoimmune hemolysis is an uncommon disorder, which can be either primary or secondary. Secondary causes include autoimmune conditions, malignancies (both hematological and non-hematological), drugs and transplantation [1]. Although the majority of patients will respond to corticosteroids a minority will need further therapy with second line options including CD20 monoclonal * Michael Sze Yuan Low low.m@wehi.edu.au

Asymptomatic refugee malaria screening - implications of using a rapid immunochromatographic antigen test only: retrospective analysis of 1248 patients

Background: Current screening guidelines for malaria in new refugees include a combination of thick and thin film examination and immunochromatographic antigen test (ICT).1 However, as the prevalence of malaria in our population has decreased due to changing refugee demographics,2,3 an immunochromatographic antigen test (ICT) alone may be sufficient to exclude malaria in asymptomatic patients. Aim: To determine if an ICT alone can reliably exclude malaria in our asymptomatic refugee population. Methods: A retrospective analysis was conducted of all investigations for malaria performed from 01/08/2011 to 31/07/2013, including external morphological and PCR validation where applicable. Results: 45 of 1248 (3.6%) patients investigated were diagnosed with malaria, all cases were in symptomatic patients. Overall 42/45 malaria cases were detected by the BinaxNOW ICT; sensitivity (95%CI) 93.3% (80.7–98.3%) and negative predictive value (NPV) 99.8% (99.2–99.9%). All 21 cases of Plasmodium falciparum were detected; sensitivity and NPV of 100% (80.8–100%) and 100% (99.6–100%), respectively. ICT detected 18/20 cases of P. vivax; sensitivity and negative predictive value of 90.9% (69.4%–98.4%) and 99.8% (99.3%–100%), respectively. Too few cases of P. malariae and no cases of P. ovale or P. knowlesis were diagnosed for adequate assessment. Discussion: These data suggest that an ICT alone may be sufficient for malaria screening in our asymptomatic refugee population.