Challenges in diagnosis and management of neutropenia upon exposure to immune-checkpoint inhibitors: meta-analysis of a rare immune-related adverse side effect.

BACKGROUND: Cancer immunotherapy via immune-checkpoint inhibition (ICI) by antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and cell death protein 1 (PD-1) have significantly improved the outcome of metastasized melanoma and of a rapidly increasing number of other cancer types. The anti-tumor effect is often accompanied by immune-related adverse events (irAE). Hematological irAE, specifically neutropenia, are rarely observed. However, neutropenia is associated with high morbidity and mortality due to infection complications. Thus, early detection and treatment is crucial. METHODS: We present the clinical course of two patients with severe neutropenia after ICI therapy and demonstrate the difficulty of the diagnosis when a comedication of metamizole, a well-known analgesic drug used to treat cancer pain, is present. Further, we provide a comprehensive descriptive and statistical analysis of published data on diagnostics, treatment and infection complication in patients with at least grade 4 neutropenia by a systematic database search. RESULTS: Finally, 34 patients were analyzed, including the two case reports from our cohort. The median onset of neutropenia was 10.5 weeks after first ICI administration (interquartile range: 6 weeks). In 76% (N = 26), a normalization of the neutrophil count was achieved after a median duration of neutropenia of 13 days. In a subsample of 22 patients with detailed data, the infection rate was 13%, proven by positive blood culture in 3 cases, but 68% (N = 15) presented with fever > 38 °C. Treatment regime differed relevantly, but mainly included G-CSF and intravenous corticosteroids. Death was reported in 14 patients (41%), 3 of whom (9%) were associated with hematological irAE but only two directly associated with neutropenia. CONCLUSION: With an increasing number of cancer patients eligible to ICI therapy, the incidence of severe hematological toxicities may rise substantially over the next years. Clinicians working in the field of cancer immune therapies should be aware of neutropenia as irAE to provide immediate treatment.

Impact of a Patient Blood Management monitoring and feedback programme on allogeneic blood transfusions and related costs.

A Patient Blood Management programme was established at the University Hospital of Zurich, along with a monitoring and feedback programme, at the beginning of 2014 with a first analysis reported in 2015. Our study aimed to investigate the further impact of this Patient Blood Management monitoring and feedback programme on transfusion requirements and related costs. We included adult patients discharged between 2012 and 2017. A total of 213,882 patients underwent analysis: 66,659 patients in the baseline period (2012-2013); 35,309 patients in the year after the introduction of the Patient Blood Management monitoring and feedback programme (2014) and 111,914 patients in the continued sustainability period (2015-2017). The introduction of the Patient Blood Management monitoring and feedback programme reduced allogeneic blood product transfusions by 35%, from 825 units per 1000 hospital discharges in 2012 to 536 units in 2017. The most sustained effect was an approximately 40% reduction in red blood cell transfusions, from 535 per 1000 discharges to 319 units. Fewer patients were transfused in the periods after the introduction of the Patient Blood Management monitoring and feedback programme (6251 (9.4%) vs. 2932 (8.3%) vs. 8196 (7.3%); p < 0.001). Compared with 2012, the yearly OR for being exposed to any blood transfusion declined steadily after the introduction of the Patient Blood Management monitoring and feedback programme to 0.64 (95%CI 0.61-0.68; p < 0.001) in 2017. For patients requiring extracorporeal membrane oxygenation, transfusion requirements were also sustainably reduced. This reduction in allogeneic blood transfusions led to savings of 12,713,754 Swiss francs (£ 9,497,000 sterling; EUR 11,100,000; US$ 12,440,000) in blood product acquisition costs over 4 years. In-hospital mortality was not affected by the programme. The Patient Blood Management monitoring and feedback programme sustainably reduced transfusion requirements and related costs, without affecting in-hospital mortality.

Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio.

Post-remission treatment (PRT) in patients with cytogenetically normal (CN) acute myeloid leukemia (AML) in first complete remission (CR1) is debated. We studied 521 patients with CN-AML in CR1, for whom mutational status of NPM1 and FLT3-ITD was available, including the FLT3-ITD allelic ratio. PRT consisted of reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) (n=68), myeloablative conditioning (MAC) alloHSCT (n=137), autologous hematopoietic stem cell transplantation (autoHSCT) (n=168) or chemotherapy (n=148). Favorable overall survival (OS) was found for patients with mutated NPM1 without FLT3-ITD (71±4%). Outcome in patients with a high FLT3-ITD allelic ratio appeared to be very poor with OS and relapse-free survival (RFS) of 23±8% and 12±6%, respectively. Patients with wild-type NPM1 without FLT3-ITD or with a low allelic burden of FLT3-ITD were considered as intermediate-risk group because of similar OS and RFS at 5 years, in which PRT by RIC alloHSCT resulted in better OS and RFS as compared with chemotherapy (hazard ratio (HR) 0.56, P=0.022 and HR 0.50, P=0.004, respectively) or autoHSCT (HR 0.60, P=0.046 and HR 0.60, P=0.043, respectively). The lowest cumulative incidence of relapse (23±4%) was observed following MAC alloHSCT. These results suggest that alloHSCT may be preferred in patients with molecularly intermediate-risk CN-AML, while the choice of conditioning type may be personalized according to risk for non-relapse mortality.

Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40-60 years.

The preferred type of post-remission therapy (PRT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1) is a subject of continued debate, especially in patients at higher risk of nonrelapse mortality (NRM), including patients >40 years of age. We report results of a time-dependent multivariable analysis of allogenic hematopoietic stem cell transplantation (alloHSCT) (n=337) versus chemotherapy (n=271) or autologous HSCT (autoHSCT) (n=152) in 760 patients aged 40-60 years with AML in CR1. Patients receiving alloHSCT showed improved overall survival (OS) as compared with chemotherapy (respectively, 57±3% vs 40±3% at 5 years, P<0.001). Comparable OS was observed following alloHSCT and autoHSCT in patients with intermediate-risk AML (60±4 vs 54±5%). However, alloHSCT was associated with less relapse (hazard ratio (HR) 0.51, P<0.001) and better relapse-free survival (RFS) (HR 0.74, P=0.029) as compared with autoHSCT in intermediate-risk AMLs. AlloHSCT was applied following myeloablative conditioning (n=157) or reduced intensity conditioning (n=180), resulting in less NRM, but comparable outcome with respect to OS, RFS and relapse. Collectively, these results show that alloHSCT is to be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged 40-60 years, whereas autoHSCT remains a treatment option to be considered in patients with intermediate-risk AML.

Allo-SCT for multiple myeloma in the era of novel agents: a retrospective study on behalf of Swiss Blood SCT.

Despite the introduction of novel drugs, cure of multiple myeloma remains rare. Allo-SCT can induce long-term remission, but randomized studies in advanced disease are lacking and the influence of novel drugs remains unclear. In our retrospective analysis of all patients with myeloma allografted in Switzerland, 95 patients were transplanted between 1988 and 2011. Most patients were heavily pre-treated, and 53% received novel drugs before transplant. In all, 51% were allografted after relapse or progression. Transplant trends changed over time with an increase in reduced intensity conditioning and unrelated donors. At the time of analysis 47 patients remained alive, with a median follow-up of survivors of 53 months. Acute GVHD II-IV and chronic GVHD (cGVHD) occurred in 49% and 53%, respectively; TRM at 5 years was 18%. Five-year OS and PFS were 51% and 29%, respectively. Patients who received transplant upfront vs after relapse had a significantly better outcome, as well as those who had a related donor and achieved CR post transplant. We found no impact of pre-treatment with novel drugs or cGVHD. Although long-term remission following allo-SCT can be achieved, GVHD and TRM remain major limitations. Our series suggests that benefit is highest when allo-SCT is used early in the disease.

Human T cell development and HIV infection in human hemato-lymphoid system mice.

Advances in generation of mice that on human hematopoietic stem and progenitor cell transplantation develop and maintain human hemato-lymphoid cells have fueled an already thriving field of research. We focus here on human T cell development and HIV infection in Rag2 -/- gamma(c) -/- mice transplanted as newborns with human CD34+ cord blood hematopoietic stem and progenitor cells.

Distinct expression pattern of IFN-alpha and TNF-alpha in juvenile idiopathic arthritis synovial tissue.

OBJECTIVES: Recent laboratory and clinical data suggest that two prototype autoimmune diseases, systemic lupus erythematosus and rheumatoid arthritis are mainly driven by distinct cytokines, interferon (IFN)-alpha and tumour necrosis factor (TNF)-alpha, respectively. We here investigated the presence and characteristics of natural type I IFN-producing cells (IPCs), as well as IFN-alpha and TNF-alpha expression at sites of inflammation in juvenile idiopathic arthritis (JIA). METHODS: Peripheral blood (PB) and synovial fluid (SF) mononuclear cells (MNCs) (n = 25 each) from JIA patients with active disease were studied. IPCs were identified as BCDA-2(+)CD123(+)HLA-DR(+)CD45RA(+) cells, and dendritic cells (DCs) as CD11c(+)CD14(-/low)lin(-) cells by flow cytometry. IPCs and DCs were analysed for Toll-like receptor-7 and -9 mRNA expression by real-time polymerase chain reaction. IFN-alpha was measured by enzyme-linked immunosorbent assay in serum, SF and in supernatants of influenza virus-infected, cultured IPCs. Synovial tissues of n = 6 additional JIA patients were analysed by immunohistochemistry using mAbs against CD123, IFN-alpha, TNF-alpha, CD3, CD19 and CD138. RESULTS: IPCs were enriched in SF MNCs compared with PB MNCs in all JIA patients. Influenza-induced, but no spontaneous IFN-alpha release was detected from SF IPCs, and serum and SF IFN-alpha levels were not elevated. Nonetheless, in synovial tissue IFN-alpha producing cells accumulated at inflammatory lymph-follicular-like structures, while TNF-alpha producing cells were mostly found at the lining and sublining layers. CONCLUSIONS: These data suggest that besides TNF-alpha-expressing cells, IFN-alpha-producing IPCs are involved in initiation, maintenance or regulation of the inflammatory response in JIA.

Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: a prospective, multicenter phase II study.

BACKGROUND: Patients with follicular (FL) or mantle cell lymphoma (MCL) are incurable with conventional therapy. We investigated the safety and efficacy of rituximab consolidation after autologous stem cell transplantation (ASCT) in order to prevent relapse by clearance of minimal residual disease (MRD). METHODS: Rituximab was given approximately 8 weeks after CD34+ cell enriched ASCT at 375 mg/m2, weekly for 4 weeks. Monitoring of MRD was performed by repetitive PCR analyses. RESULTS: Thirty-one patients were included; one died early after ASCT before rituximab administration. Thirty patients (20 FL, 10 MCL) were evaluable after rituximab consolidation, and 27 of these were assessable for MRD detection. Rituximab consolidation post-ASCT was safe, the most common toxicity being infection. At a median follow-up of 42 months (range 13-96) after ASCT, 25 patients were censored with an actuarial event-free survival (EFS) of 81% at 4 and 5 years. Four patients (two FL, two MCL) relapsed, and one additional MCL patient died unexpectedly in complete remission. PCR-negativity was observed in 22% of the patients before ASCT, 53% post-ASCT (P=0.0547), 72% after rituximab (P=0.0018) and 100% at 6 months post-transplant (P < 0.001). CONCLUSIONS: One single course of rituximab consolidation given after ASCT is safe, may help to eliminate MRD and may translate into improved EFS in both FL and MCL patients.

Lymphocyte development from hematopoietic stem cells.

The recent application of new techniques, such as multi-color cell sorting and the production of transgenic and gene-knockout mice, has contributed to a better understanding of lymphocyte development from hematopoietic stem cells. Now that we can purify progenitors at different maturational stages during lymphocyte development, the challenge is to understand the processes that govern each developmental stage transition.

Dendritic cell development from common myeloid progenitors.

Dendritic cells (DCs) are professional antigen-presenting cells which both initiate adaptive immune responses and control tolerance to self-antigens. It has been suggested that these different effects on responder cells depend on subsets of DCs arising from either myeloid or lymphoid hematopoietic origins. In this model, CD8 alpha+ Mac-1- DCs are supposed to be of lymphoid while CD8 alpha- Mac-1+ DCs are supposed to be of myeloid origin. Here we summarize our findings that both CD8 alpha+ and CD8 alpha- DCs can arise from clonogenic common myeloid progenitors (CMPs) in both thymus and spleen. Therefore CD8 alpha expression DCs does not indicate a lymphoid origin and differences among CD8 alpha+ and CD8 alpha- DCs might rather reflect maturation status than ontogeny. On the basis of transplantation studies, it seems likely that most of the DCs in secondary lymphoid organs and a substantial fraction of thymic DCs are myeloid-derived.

Dendritic cell potentials of early lymphoid and myeloid progenitors.

It has been proposed that there are at least 2 classes of dendritic cells (DCs), CD8alpha(+) DCs derived from the lymphoid lineage and CD8alpha(-) DCs derived from the myeloid lineage. Here, the abilities of lymphoid- and myeloid-restricted progenitors to generate DCs are compared, and their overall contributions to the DC compartment are evaluated. It has previously been shown that primitive myeloid-committed progenitors (common myeloid progenitors [CMPs]) are efficient precursors of both CD8alpha(+) and CD8alpha(-) DCs in vivo. Here it is shown that the earliest lymphoid-committed progenitors (common lymphoid progenitors [CLPs]) and CMPs and their progeny granulocyte-macrophage progenitors (GMPs) can give rise to functional DCs in vitro and in vivo. CLPs are more efficient in generating DCs than their T-lineage descendants, the early thymocyte progenitors and pro-T cells, and CMPs are more efficient DC precursors than the descendant GMPs, whereas pro-B cells and megakaryocyte-erythrocyte progenitors are incapable of generating DCs. Thus, DC developmental potential is preserved during T- but not B-lymphoid differentiation from CLP and during granulocyte-macrophage but not megakaryocyte-erythrocyte development from CMP. In vivo reconstitution experiments show that CLPs and CMPs can reconstitute CD8alpha(+) and CD8alpha(-) DCs with similar efficiency on a per cell basis. However, CMPs are 10-fold more numerous than CLPs, suggesting that at steady state, CLPs provide only a minority of splenic DCs and approximately half the DCs in thymus, whereas most DCs, including CD8alpha(+) and CD8alpha(-) subtypes, are of myeloid origin. (Blood. 2001;97:3333-3341)

Myasthenia gravis and tumor necrosis factor beta polymorphisms: linkage disequilibrium but no association beyond HLA-B8.

Tumor necrosis factor (TNF) may contribute to the susceptibility for autoimmune diseases. We examined TNFbeta gene polymorphisms detected by AspHI and NcoI digestion of genomic DNA in patients with myasthenia gravis (n=105) and healthy controls (n=114). In both groups, the frequencies of TNFbeta alleles were not different. AspHI and NcoI polymorphisms of TNFbeta showed a strong association with HLA-B8 (p < 0.03 resp. p < 0.0001 for AspHI and Ncol) both in patients and controls. Our results imply linkage disequilibrium of TNFbeta alleles with HLA-B8 and in myasthenia gravis we were unable to show a stronger association beyond HLA-B8.