SummaryConsolidation with high dose chemotherapy and autologous stem cell transplantation (ASCT) is the standard of care for transplant eligible patients with multiple myeloma, based on randomised trials showing improved progression free survival with autologous transplantation following combination chemotherapy induction. These trials were performed before novel agents were introduced, and subsequently combinations of immunomodulatory drugs (IMiDs) and proteasome inhibitors as induction therapy have significantly improved rates and depth of response. Ongoing randomised trials are testing whether conventional autologous transplantation continues to improve responses following novel agent induction. While these results are awaited, it is important to review strategies for improving outcomes following ASCT. Conditioning prior to ASCT with higher doses of melphalan, and combinations of melphalan with other agents, including radiopharmaceuticals have been explored. Tandem ASCT, consolidation and maintenance therapy following ASCT have been investigated in phase III trials. Experimental cellular therapies using ex vivo primed dendritic cells , ex vivo expanded autologous lymphocytes, KIR-mismatched allogeneic NK cells, and genetically modified T cells are also in phase I trials to augment ASCT. This review summarises these strategies and highlights the importance of exploring strategies to augment ASCT even in the era of novel agent induction.
A 66-year-old man presented with fevers, myalgia, weight loss and an urticarial rash. A full blood count showed haemoglobin concentration 70 g/l and white cell count 1Á7 9 10 9 /l with rouleaux and lymphoplasmacytoid lymphocytes seen in the blood film. He was positive for anti-neutrophil cytoplasmic antibodies (cANCA) and anti-proteinase 3 (weakly). Parvovirus immunoglobulin (Ig) M and IgG antibodies were detected, but polymerase chain reaction (PCR) for parvovirus DNA was negative. A computed tomography (CT) scan demonstrated widespread lymphadenopathy and hepatosplenomegaly (top left). A lymph node biopsy showed proliferation of capillaries with an infiltrate of small to medium sized atypical lymphocytes admixed with eosinophils, plasma cells and large blasts (bottom left). These lymphocytes were CD2 + CD3 + CD5 + with the blasts being CD10 + on immunohistochemistry, confirming a diagnosis of angioimmunoblastic T-cell lymphoma (AITL). Prior to starting treatment, the symptoms improved spontaneously with normalisation of his full blood count. Repeat CT imaging 5 months after the initial presentation confirmed complete remission (top centre).He remained well for 52 months before re-presenting with a similar symptom complex, including rash, sweats and weight loss, with widespread lymphadenopathy and splenomegaly on CT imaging (top right). Serological tests for human immunodeficiency virus (HIV) and human T-cell lymphotropic virus 1 (HTLV1) were positive, but an HIV line immunoassay and HTLV1 PCR confirmed neither infection was present. A lymph node biopsy showed increased blood vessels with a polymorphous lymphoid infiltrate, including some blasts, and numerous eosinophils (bottom right). The blasts co-expressed CD10 and PD-1 (also termed PDCD1) on immunohistochemistry, consistent with relapsed AITL. The patient was subsequently commenced on combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) achieving a very good partial response after four cycles.AITL is frequently associated with abnormal immune phenomena, such as inflammatory rashes and false positive serology results. Spontaneous remissions are rare and usually short-lived, with a median of 9 months (Pangalis et al, 1983) but, as shown in our patient, can be more sustained.
We report two British cases of liver abscess, due to Klebsiella pneumoniae and associated with synchronous infection elsewhere, which required liver resection for definitive treatment. They illustrate the geographic spread of aggressive K pneumoniae liver infection and demonstrate the importance of early aggressive treatment.
Introduction: A small proportion of large B cell non-Hodgkin lymphoma (NHL) has MYC and BCL6 rearrangements, detectable by fluorescence in-situ hybridisation (FISH) break-apart probes. There
R-CHOP chemoimmunotherapy has been the standard of care for diffuse large B cell lymphoma (DLBCL) for 20 years. The lymphoma and microenvironment responses to R-CHOP have not been studied in detail in an experimental setting. Here we describe the early effects of R-CHOP on lymphoma cells and infiltrating T cells in novel mouse models of DLBCL. Using cre-lox recombination to induce B cell-specific overexpression of MYC, IKK2 and BLIMP1 drives the formation of unique high grade B cell lymphomas with an activated B cell (ABC) phenotype and an intact immune environment. Using flow cytometry and RNA sequencing we compare the response to R-CHOP in these mice with the response in a cell line lymphoma model. We also performed partial splenectomy prior to R-CHOP treatment to study paired samples pre-treatment and at relapse by whole-exome and RNA sequencing. Treatment with anti-CD20 alone induced very few changes in lymphoma cells in either model, but CHOP chemotherapy in combination with rituximab induced changes in lymphoma cell and T cell phenotypes. In particular, extracellular matrix and cell adhesion gene signatures were enriched in lymphoma cells after treatment, in both disease models studied. After injection of the cell line, memory populations of CD8+ T cells are expanded but this change is reversed by chemotherapy, whereas in the cre-lox conditional model 40% of CD8+ T cells are exhausted with smaller chemotherapy-associated changes. In the paired pre-treatment/relapse samples we observed clonal selection and increased mutation burden at relapse, associated with diverse transcriptional changes. Mutations were newly detected or expanded at relapse in various lymphoma-associated genes including Trp53, Samhd1 and Ubr5. Our results suggest that DLBCL responses to treatment and biology at relapse are principally driven by tumour-specific factors, but there are some commonalities across model systems which may be amenable to therapeutic modulation. The differences in T cell responses between conditional tumours and cell-line tumours demonstrate the limitations of cell lines for studying treatment responses in vivo.
Figure 1 Figure 1.
Disclosures
Johnson: Boehringer Ingelheim: Consultancy; Janssen: Consultancy; Kite Pharma: Honoraria; Oncimmune: Consultancy; Epizyme: Consultancy, Research Funding; Bristol-Myers: Honoraria; Incyte: Honoraria; Genmab: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Morphosys: Honoraria; Celgene: Honoraria; Kymera: Honoraria. Fitzgibbon: Epizyme: Research Funding. Calado: Myricx Pharma: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties: Cancer Treatments. WO patent WO 2020/128475 A1 (2020).
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