Kah-Lok Chan

Rituximab is associated with improved survival for aggressive B cell CNS lymphoma

BACKGROUND The optimal treatment strategy in patients with aggressive B cell central nervous system lymphoma suitable to receive intensive therapy is unknown. The benefit of incorporating rituximab in systemic therapy remains unclear. We performed a retrospective study examining the impact of rituximab in the context of concomitant therapies, including methotrexate, cytarabine, and radiotherapy, in patients treated with curative intent at 4 university teaching hospitals during 1996-2011. METHODS A retrospective study of CNS lymphoma cases treated at the participating institutions was performed in accordance with institutional ethical guidelines. Patients were included if they received a diagnosis of primary diffuse large B cell lymphoma of the CNS, were HIV negative, and were treated with curative intent. RESULTS One hundred twenty patients aged 21-81 years were identified. Rituximab recipients and nonrecipients were similar, except for rituximab recipients being more likely to have received a diagnosis after 2004. The median follow-up of surviving patients was 30 months. The 5-year overall survival was 46%. Univariate analysis revealed age ≤60 years, ECOG performance status ≤1, normal lactate dehydrogenase, diagnosis after 2004, and treatment with cytarabine and rituximab as predictive of favorable overall survival. Multivariate analysis identified age to be an independent predictor of overall survival, with a trend toward improved survival from the other variables that were significant in univariate analyses. CONCLUSIONS In this retrospective analysis, the addition of rituximab to high-dose methotrexate-based chemotherapy in patients with aggressive B cell CNS lymphoma was associated with improved overall survival. Further studies are underway to prospectively validate these findings.

Update and new approaches in the treatment of Castleman disease

First described 60 years ago, Castleman disease comprises a rare and heterogeneous cluster of disorders, characterized by lymphadenopathy with unique histological features and associated with cytokine-driven constitutional symptoms and biochemical disturbances. Although unicentric Castleman disease is curable with complete surgical excision, its multicentric counterpart is a considerable therapeutic challenge. The recent development of biological agents, particularly monoclonal antibodies to interleukin-6 and its receptor, allow for more targeted disease-specific intervention that promises improved response rates and more durable disease control; however, further work is required to fill knowledge gaps in terms of underlying pathophysiology and to facilitate alternative treatment options for refractory cases.

‘Real-world’ Australian experience of pomalidomide for relapsed and refractory myeloma

Ashleigh Scott , Nicholas Weber, Campbell Tiley, Kerry Taylor, John Taper, Simon Harrison, Kah-Lok Chan, Richard Stark, Cindy Lee, Kirk Morris, P. Joy Ho, Anthony Dodds, Sundra Ramanathan, Raj Ramakrishna, Anne-Marie Watson, Bradley Auguston, Fiona Kwok, Hang Quach, Pauline Warburton, Philip Rowlings and Peter Mollee Princess Alexandra Hospital, Woollongabba, Brisbane, Australia; University of Queensland, St Lucia, Brisbane, Australia; Royal Brisbane and Women’s Hospital, Herston, Brisbane, Australia; Gosford Hospital, Gosford, New South Wales, Australia; Icon Cancer Care, South Brisbane, Australia; Nepean Hospital, Nepean, Sydney, Australia; Peter MacCallum Cancer Centre, Melbourne, Australia; Port Macquarie Base Hospital, Port Macquarie, New South Wales, Australia; Royal Adelaide Hospital, Queen Elizabeth Hospital, Adelaide, Australia; Royal Prince Alfred Hospital, Sydney, Australia; St Vincent’s Hospital, Sydney, Australia; St George Hospital, Kogarah, Sydney, Australia; Southern Sydney Haematology, Kogarah, Sydney, Australia; Liverpool Hospital, Liverpool, Sydney, Australia; Sir Charles Gairdner Hospital, Perth, Australia; Westmead Hospital, Sydney, Australia; St Vincent’s Hospital, Melbourne, Australia; Wollongong Hospital, Wollongong, New South Wales, Australia; Calvary Mater Hospital, Newcastle, New South Wales, Australia

Plasmablastic Richter transformation as a resistance mechanism for chronic lymphocytic leukaemia treated with BCR signalling inhibitors

Auger, S., Duny, Y., Rossi, J.F. & Quittet, P. (2012) Rituximab before splenectomy in adults with primary idiopathic thrombocytopenic purpura: a meta-analysis. British Journal of Haematology, 158, 386–398. Barmparas, G., Lamb, A.W., Lee, D., Nguyen, B., Eng, J., Bloom, M.B. & Ley, E.J. (2015) Postoperative infection risk after splenectomy: a prospective cohort study. International Journal of Surgery, 17, 10–14. Chen, J., Ma, R., Yang, S., Lin, S., He, S. & Cai, X. (2014) Perioperative outcomes of laparoscopic versus open splenectomy for nontraumatic diseases: a meta-analysis. Chinese Medical Journal (English Language), 127, 2504–2510. Clavien, P.A., Barkun, J., de Oliveira, M.L., Vauthey, J.N., Dindo, D., Schulick, R.D., de Santiba~ nes, E., Pekolj, J., Slankamenac, K., Bassi, C., Graf, R., Vonlanthen, R., Padbury, R., Cameron, J.L. & Makuuchi, M. (2009) The Clavien-Dindo classification of surgical complications: five-year experience. Annals of Surgery, 250, 187–196. Davidson, R.N. & Wall, R.A. (2001) Prevention and management of infections in patients without a spleen. Clinical Microbiology and Infection, 7, 657–660. NICE (2013) Eltrombopag for treating chronic immune (idiopathic) thrombocytopenic purpura (review of technology appraisal 205): National Institute for Health and Care Excellence. Available at http://guidance.nice.org.uk/TA293 [Accessed March 13, 2016]. NICE (2014) Immune (idiopathic) thrombocytopenic purpura: rituximab: National Institute for Health and Care Excellence. Available at https://www.nice.org.uk/advice/esuom35/chapter/key-points-from-the-evidence [Accessed March 13, 2016]. Nyilas, A., Paszt, A., Simonka, Z., Abrah am, S., Borda, B., M an, E. & L az ar, G. (2015) Laparoscopic splenectomy is a safe method in cases of extremely large spleens. Journal of Laparoendoscopic Advanced Surgical Techniques, 25, 212–216. Patel, V. L., Mah evas, M., Lee, S. Y., Stasi, R., Cunningham-Rundles, S., Godeau, B., Kanter, J., Neufeld, E., Taube, T., Ramenghi, U., Shenoy, S., Ward, M. J., Mihatov, N., Patel, V. L., Bierling, P., Lesser, M., Cooper, N. & Bussel, J. B. (2012) Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood, 119, 5989–5995 Taniguchi, L.U., Correia, M.D. & Zampieri, F.G. (2014) Overwhelming post-splenectomy infection: narrative review of the literature. Surgical Infections, 15, 686–693.

Durable clinical remission induced by romidepsin for chemotherapy-refractory peripheral T-cell lymphoma with central nervous system involvement

The peripheral T-cell lymphomas (PTCL) comprise a diverse range of hematological neoplasms, accounting for 10–15% of all non-Hodgkin lymphomas diagnosed in adults [1] and typically possessing an ag...

Central nervous system immune reconstitution inflammatory syndrome after ibrutinib therapy for Richter transformation.

The immune reconstitution inflammatory syndrome (IRIS) describes emergence or paradoxical inflammatory worsening of infectious phenomena, classically after initiating anti-retroviral therapy in patients infected with human immunodeficiency virus (HIV).[1,2] IRIS has also been described in non-HIV-infected patients receiving lymphocyte-depleting therapy, including alemtuzumab (where Cryptococcus neoformans was the triggering pathogen) [3] and rituximab (Mycobacterium tuberculosis).[4] We present a patient with chemotherapy/rituximab-refractory, transformed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who developed a widespread, inflammatory process involving cerebral white matter, which occurred in the context of recent cytomegalovirus (CMV) viremia, initiation of ibrutinib and concurrent recovery from severe lymphopenia; after exclusion of all other pathogenic processes on brain biopsy, a clinicopathological diagnosis of IRIS was made and the patient responded appropriately to corticosteroid therapy. A 61-year-old man was diagnosed with CLL/SLL in January 2008 after presenting with right supraclavicular lymphadenopathy, in the absence of significant lymphocytosis. He was treated with intermittent chlorambucil and prednisolone until July 2013, when he developed progressive axillary lymphadenopathy. Six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) were administered, with partial and transient response. He received six further cycles of R-CHOP from June 2014, but had disease progression three months after completion of therapy. One cycle of FCR (fludarabine, cyclophosphamide and rituximab) was administered, resulting in partial regression of his axillary lymphadenopathy; however, rapid enlargement of cervical and supraclavicular lymph nodes was then noted. Cervical lymph node biopsy revealed a diffuse infiltrate of large lymphoid cells, with the immunophenotype of CD20þ, CD5þ (focal/weak), CD10, CD23þ, BCL-2þ, BCL-6, cyclin D-1, MUM-1þ, consistent with Richter transformation to diffuse large B-cell lymphoma (DLBCL), activated B-cell (ABC) subtype. In situ hybridization testing for Epstein–Barr virus (EBV) was negative. Staging positron emission tomography (PET) scanning showed extensive, generalized lymphadenopathy, with nodal conglomerates measuring up to 15 cm in maximal diameter. Bone marrow biopsy demonstrated 10–15% involvement by CLL/ SLL, with no evidence of large cell lymphoma. Fluorescence in situ hybridization (FISH) testing on bone marrow identified deletions of 13q14 and 17p13 in 7 and 10% of cells scored, respectively, while molecular testing also detected mutations in NOTCH1 (c.7541_7542del) and SF3B1 (c.1997A>C). The patient’s lymphoma was refractory to two cycles of high-dose intravenous methotrexate and cytarabine (B cycle of Hyper-CVAD),[5] as well as one cycle of GDP (gemcitabine, dexamethasone and cisplatin). Emergence of CMV viremia was noted during this time and treated with four weeks of intravenous ganciclovir. He also developed severe thrombocytopenia, which persisted despite clearance of CMV viremia, high-dose corticosteroids, intravenous immunoglobulin, and romiplostim. Repeat bone marrow biopsy demonstrated an unchanged burden of CLL/SLL and preserved megakaryopoiesis, consistent with peripheral platelet destruction and/or sequestration. Immune thrombocytopenia secondary to CLL/SLL was suspected. Ibrutinib was commenced at 140 mg daily, due to the patient’s severe thrombocytopenia, and escalated to 420 mg daily over a period of two weeks. Despite intensive platelet support, he developed a 2.5 cm left occipital hemorrhage with associated hemianopia, which was managed conservatively and without ibrutinib interruption. Magnetic resonance imaging (MRI) of his brain one month later demonstrated stable hematoma size, with no evidence of underlying mass lesion. Ibrutinib was continued, resulting in complete response from DLBCL as demonstrated on repeat PET scanning two months after

The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia

Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation. Age and dose were risk factors for pleural effusion (P < .01 and .047, respectively). Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced (P = .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions (P = .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.