Michael Low

Central nervous system multiple myeloma--potential roles for intrathecal therapy and measurement of cerebrospinal fluid light chains.

Central nervous system (CNS) multiple myeloma (MM) is exceedingly rare and portends a dismal prognosis. While immunomodulators have contributed to the improvement in survival in MM, they appear to have limited activity against CNS MM and, paradoxically, may contribute to the evolution of resistant MM clones capable of surviving within the CNS. We undertook a retrospective analysis to characterize the features of CNS MM and outcome in 17 patients from four institutions identified between 2000 and 2011. The median age was 58 years. Patients had received a median of three prior therapies and all had been exposed to at least one of the so‐called novel anti‐MM agents before the diagnosis of CNS MM. The median time to CNS disease from initial diagnosis was 36 months. Cerebrospinal fluid (CSF) light chain measurements produced discrepant results to serum light chain measurements in some patients. Treatments included systemic pharmacotherapy, intrathecal (IT) chemotherapy and/or radiotherapy (RT). The median overall survival (OS) from diagnosis of CNS MM was only 4 months. OS was significantly better in patients who received IT chemotherapy (20 months vs. 2 months, respectively; P < 0·02). We conclude that the systematic evaluation of IT therapy and diagnostic utility of CSF light chain measurements in CNS MM are warranted.

High-dose cytarabine (24 g/m2) in combination with idarubicin (HiDAC-3) results in high first-cycle response with limited gastrointestinal toxicity in adult acute myeloid leukaemia.

Although induction chemotherapy comprising high‐dose cytarabine (HiDAC) in combination with idarubicin and etoposide or ‘ICE’ for adult acute myeloid leukaemia (AML) produces a complete remission rate of nearly 80%, gastrointestinal toxicity is significant. Omission of etoposide may produce similar clinical outcomes with potentially less gastrointestinal toxicity.

Detectable CD8 cells correlate with improved overall survival in adult B lymphoblastic leukaemia patients

Adult B acute lymphoblastic leukaemia (B-ALL) is historically a poor prognostic disease with 5-year overall survival around 35%. Treatment paradigms are based on risk stratification, with high or very high-risk patients generally considered for allogeneic bone marrow transplantation to minimize the risk of relapsed disease, which portends a dismal prognosis. In contrast, patients with standard risk are often not transplanted in first complete remission to reduce treatment-related mortality. Despite this, the 5-year disease-free survival of standard risk patients is only 50–60%, with around 35% of standard risk patients relapsing (Bassan & Hoelzer, 2011). These numbers highlight a need for ongoing improvements in the prognostication of B-ALL patients to guide treatment policies. New therapeutic approaches for B-ALL have recently emerged, several of which have shown promising preliminary results. In particular, two therapies that utilize autologous T cells have demonstrated efficacy in relapsed/refractory patients and have established a definite role for T cells in B-ALL treatment. The first, Blinatumomab, is a bi-specific T cell engaging (BiTE) antibody that localizes and activates CD3 T cells against CD19-positive leukaemic cells with efficacy in phase 1 and 2 trials (Portell & Advani, 2012). The second therapy uses chimeric antigen receptor-modified T cells (CAR) with modified CD28/CD3 targeting anti-CD19 regions and leads to T cell activation against B-ALL cells, which has recently shown efficacy in a case series of chemotherapy refractory B-ALL patients (Brentjens et al, 2013). Additionally, T cell concentrations in diagnostic biopsies correlate with prognosis in numerous solid tumours and lymphoma (Bindea et al, 2011). The aim of the present study was to enumerate T cell numbers on trephine biopsies of adult B-ALL patients and determine whether T cell numbers could be used to prognosticate patients. This research was approved by the Alfred Hospital Ethics Committee (Project Number 125/13). Diagnostic trephine biopsies of all patients treated at The Alfred Hospital, Melbourne, Australia for B-ALL between 2005 and 2012 were retrospectively assessed. Using immunohistochemistry, trephines were stained with CD3, CD4, CD8, FOXP3 and Granzyme B antibodies. Three images were taken at 9200 objective and cells were quantified by an imaging analysis program developed for Fiji software (v 1.46; Schindelin et al, 2012). The program was validated on five randomly chosen patient trephine sections by two independent and blinded morphologists. Samples were graded either virtually undetectable (<1% positive cells) or detectable (>1% positive cells). Morphology and the imaging program had a 92% correlation. Thirty-three patients were identified. Median follow up for all patients was 5 years. All patients were treated at clinician discretion. Patients with detectable CD8-positive cells (n = 16) at diagnosis had improved overall survival compared to those with undetectable CD8 (n = 17) with a median overall survival: not reached versus 488 d (Fig 1). There was a trend to higher relapse rates in the CD8 undetectable group (2 vs. 8; P = 0 06). There was no statistically significant difference between detectable and undetectable CD8 groups in standard adverse prognostic characteristics (Table I). There was also no difference in the number of patients undergoing allogeneic bone marrow transplantation (6 vs. 5 patients; P = 0 72). There was no difference in survival between those with detectable or non-detectable CD3, CD4, FOXP3 and Granzyme B. To the best of our knowledge, this study is the first to demonstrate a positive correlation with detectable CD8 T cells on trephine biopsies of B-ALL patients and survival. One explanation is that tumour-mediated suppression of T cell numbers, particularly CD8 T cells, may represent a method of immune evasion. Cytokine changes have been observed in patients with B-ALL and these changes can modulate the immune system’s anti-tumour effects (Gros et al, 2006). Similarly, other studies have shown that B-ALL can have variable expression of surface markers, including CD70 and CD137, that can effect T helper 1 response, which stimulates CD8 cytotoxic T cells (Barbaric et al, 2005; Glouchkova et al, 2009) Taken together, these studies suggest that B-ALL may induce changes that cause immune evasion. Alternatively, undetectable CD8 T cell

Iron deficiency and new insights into therapy.

Iron deficiency and iron deficiency anaemia remain prevalent in Australia. The groups at highest risk are pre-menopausal women, socially disadvantaged people and those of Indigenous background. Diagnosing iron deficiency using a full blood examination and iron studies can be difficult and can be further complicated by concomitant inflammation. Results of iron studies should always be interpreted as an overall picture rather than focusing on individual parameters. In difficult clinical scenarios, soluble transferrin receptor assays can be useful. Management of iron deficiency involves identification and treatment of the cause of iron deficiency, as well as effective iron replacement. Clinicians should always take a detailed history and perform a comprehensive physical examination of a patient with iron deficiency. Patients should be monitored even if a likely cause of iron deficiency is identified. Patients who fail to respond to iron replacement or maintain iron status should be referred for further investigation, including endoscopy to exclude internal bleeding. Both enteral and parenteral iron are effective at replacing iron. For most adult patients, we recommend trialling daily oral iron (30-100 mg of elemental iron) as the first-line therapy. Safety and efficacy of intravenous iron infusions have improved with the availability of a newer formulation, ferric carboxymaltose. Patients who fail to respond to oral iron replacement can be safely managed with intravenous iron. Blood transfusion for iron deficiency anaemia should be reserved for life-threatening situations and should always be followed by appropriate iron replacement.

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.

Targeting plasma cells: are we any closer to a panacea for diseases of antibody-secreting cells?

Antibody‐secreting cells (ASCs) are critical for a functional and effective adaptive immune system. In a number of illnesses, however, these same cells contribute to the underlying disease state leading to significant morbidity and mortality. While therapeutic targeting of antibody‐secreting cells has progressed significantly over the last two decades, many of these conditions remain major health problems. In this review, we will discuss current and potential therapeutic targeting of ASCs in the context of the known biology of these cells.

Lyn, Lupus, and (B) Lymphocytes, a Lesson on the Critical Balance of Kinase Signaling in Immunity

Systemic lupus erythematosus (SLE) is a progressive autoimmune disease characterized by increased sensitivity to self-antigens, auto-antibody production, and systemic inflammation. B cells have been implicated in disease progression and as such represent an attractive therapeutic target. Lyn is a Src family tyrosine kinase that plays a major role in regulating signaling pathways within B cells as well as other hematopoietic cells. Its role in initiating negative signaling cascades is especially critical as exemplified by Lyn−/− mice developing an SLE-like disease with plasma cell hyperplasia, underscoring the importance of tightly regulating signaling within B cells. This review highlights recent advances in our understanding of the function of the Src family tyrosine kinase Lyn in B lymphocytes and its contribution to positive and negative signaling pathways that are dysregulated in autoimmunity.

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 CRISPR-Cas9 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 remodeling 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.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

Periorbital papules as a presenting sign in multiple myeloma with AL amyloidosis

A 67-year-old woman of Indian heritage with no significant medical history presented with a 9-month history of progressive periorbital lesions consisting of coalescing pigmented papules (figure 1A). On systems review she reported concurrent diarrhoea and weight loss. She was not in overt heart failure and had no other cutaneous lesions or macroglossia.nnnnFigurexa01 n(A) Confluent periorbital lesions. (B) Deposition of pink amorphous material on histological section