Helena Pomares

Impact of prior rituximab on outcomes of autologous stem-cell transplantation in patients with relapsed or refractory aggressive B-cell lymphoma: a multicentre retrospective Spanish group of lymphoma/autologous bone marrow transplant study.

The use of highly effective rituximab‐containing therapy for treating diffuse large B‐cell lymphoma (DLBCL) makes it more difficult to salvage relapsed or refractory patients. Autologous stem‐cell transplantation (ASCT) is the reference treatment for these patients, but the impact of previous exposure to rituximab on the subsequent results of ASCT remains unknown. We analysed 248 patients with relapsed or refractory DLBCL or grade 3B follicular lymphoma pre‐treated with rituximab as part of first‐line therapy (R+ group) who received ASCT, in comparison with a control group of 127 patients without previous exposure to rituximab (R− group). The complete remission (CR) rates were similar in both groups. Multivariate analysis identified age‐adjusted International Prognostic Index at diagnosis, extranodal involvement and disease status at transplant, and the number of previous chemotherapy lines as independent factors with a negative influence on CR rate. Compared with R− patients, those in the R+ group had a significantly better progression‐free survival (63% vs. 48% at 5 years) and overall survival (72% vs. 61% at 5 years). This observation was independent of other prognostic factors that affected these outcomes. In conclusion, ASCT is no less effective in patients with relapsed or refractory aggressive B‐cell lymphoma pre‐treated with first‐line rituximab‐containing therapy than in rituximab‐naive patients.

Blastic plasmacytoid dendritic cell neoplasm frequently shows occult central nervous system involvement at diagnosis and benefits from intrathecal therapy

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid neoplasm which shows a high rate of central nervous system (CNS) recurrence and overall survival (OS) of <1 year. Despite this, screening for CNS involvement is not routinely performed at diagnosis and intrathecal (IT) prophylaxis is not regularly administered in BPDCN. Here, we prospectively evaluated 13 consecutive BPDCN patients for the presence of CNS involvement by flow cytometry. Despite none of the patients presented with neurological symptoms, occult CNS involvement was detected in 6/10 cases evaluated at diagnosis and 3/3 studied at relapse/progression. BPDCN patients evaluated at diagnosis received IT treatment -either CNS prophylaxis (n = 4) or active therapy (n = 6)- and all but one remain alive (median follow-up of 20 months). In contrast, all three patients assessed at relapse/progression died. The potential benefit of IT treatment administered early at diagnosis on OS and CNS recurrence-free survival of BPDCN was further confirmed in a retrospective cohort of another 23 BPDCN patients. Our results show that BPDCN patients studied at diagnosis frequently display occult CNS involvement; moreover, they also indicate that treatment of occult CNS disease might lead to a dramatically improved outcome of BPDCN.

Invasive fungal infections in AML/MDS patients treated with azacitidine: a risk worth considering antifungal prophylaxis?

The aim of this study is to analyse the risk of invasive fungal infection (IFI) and the need for antifungal prophylaxis in patients with acute myeloid leukaemia and myelodysplastic syndromes (AML/MDS) treated with azacitidine. We retrospectively analysed the incidence of IFI according to EORTC‐MSG criteria in 121 consecutive AML/MDS patients receiving 948 azacitidine courses (median 5, range 1–43) between June 2007 and June 2015. Four cases of IFI (two possible, one probable aspergillosis and one proven candidemia) occurred in this series. The incidence rate of proven/probable IFI was 0.21% per treatment cycle and 1.6% per patient treated for the whole series, and 0.73% per treatment cycle and 4.1% per patient treated in those with severe neutropenia. Two patients died from IFI, leading to an IFI‐attributable mortality rate of 1.65% per patient and 0.21% per treatment cycle. The numbers needed to treat with prophylaxis to prevent one case of IFI are 238 azacitidine cycles or 30 patients throughout their whole treatment course, and 137 azacitidine cycles or 24 patients among those with severe neutropenia. AML/MDS patients treated with azacitidine, including those with severe prolonged neutropenia, have a very low risk of IFI which does not justify the use of antifungal prophylaxis.

Refractoriness to immunochemotherapy in follicular lymphoma: Predictive factors and outcome

Follicular lymphoma is characterized by a good response to immunochemotherapy (ICT). However, a small percentage of patients responds poorly to treatment and seems to have a worse outcome. This study attempted to identify the predictive factors and outcome of refractoriness to first‐line ICT. All patients diagnosed with stage II to IV follicular lymphoma between 2002 and 2014 and treated with first‐line ICT in 4 Spanish institutions were analyzed. Those with no response or progression or relapse within 6 months of first‐line response assessment were considered ICT refractory. Three hundred forty‐three patients were included (median age 58 years, 48% male), of whom 53 (15%) were ICT refractory. On multivariate analysis, high‐risk follicular lymphoma international prognostic index (FLIPI) score, B symptoms, and elevated β2‐microglobulin were correlated with refractoriness, and refractoriness, high‐risk FLIPI score, and β2‐microglobulin were correlated with overall survival (OS). Compared with ICT‐sensitive, ICT‐refractory patients had a higher incidence of histological transformation (5‐year cumulative incidence 25% [14%‐39%] vs. 6% [3%‐10%], P < .001), a higher rate of refractoriness to second‐line therapy (16/33 [48%] vs. 13/57 [23%], P = .01), and a lower OS (5‐year OS probability 38% [95% CI 23%‐53%] vs. 87% [82%‐92%%], P < .001). In conclusion, refractoriness to ICT was seen in 15% of patients and was predicted by high‐FLIPI scores, B symptoms, and elevated serum β2‐micrglobulin. Immunochemotherapy‐refractory patients had a worse prognosis than ICT‐sensitive patients, and current treatment options for this subgroup are not satisfactory.

Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features

Clonal cytogenetic abnormalities are found in 20-30% of patients with chronic myelomonocytic leukemia (CMML), while gene mutations are present in >90% of cases. Patients with low risk cytogenetic features account for 80% of CMML cases and often fall into the low risk categories of CMML prognostic scoring systems, but the outcome differs considerably among them. We performed targeted deep sequencing of 83 myeloid-related genes in 56 CMML patients with low risk cytogenetic features or uninformative conventional cytogenetics (CC) at diagnosis, with the aim to identify the genetic characteristics of patients with a more aggressive disease. Targeted sequencing was also performed in a subset of these patients at time of acute myeloid leukemia (AML) transformation. Overall, 98% of patients harbored at least one mutation. Mutations in cell signaling genes were acquired at time of AML progression. Mutations in ASXL1, EZH2 and NRAS correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS). Patients with SRSF2 mutations associated with poorer OS, while absence of TET2 mutations (TET2wt) was predictive of shorter PFS. A decrease in OS and PFS was observed as the number of adverse risk gene mutations (ASXL1, EZH2, NRAS and SRSF2) increased. On multivariate analyses, CMML-specific scoring system (CPSS) and presence of adverse risk gene mutations remained significant for OS, while CPSS and TET2wt were predictive of PFS. These results confirm that mutation analysis can add prognostic value to patients with CMML and low risk cytogenetic features or uninformative CC.

A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation

We previously described diaryl trifluorothiazoline compound 1a (hereafter referred to as fluorizoline) as a first-in-class small molecule that induces p53-independent apoptosis in a wide range of tumor cell lines. Fluorizoline directly binds to prohibitin 1 and 2 (PHBs), two proteins involved in the regulation of several cellular processes, including apoptosis. Here we demonstrate that fluorizoline-induced apoptosis is mediated by PHBs, as cells depleted of these proteins are highly resistant to fluorizoline treatment. In addition, BAX and BAK are necessary for fluorizoline-induced cytotoxic effects, thereby proving that apoptosis occurs through the intrinsic pathway. Expression analysis revealed that fluorizoline induced the upregulation of Noxa and Bim mRNA levels, which was not observed in PHB-depleted MEFs. Finally, Noxa−/−/Bim−/− MEFs and NOXA-downregulated HeLa cells were resistant to fluorizoline-induced apoptosis. All together, these findings show that fluorizoline requires PHBs to execute the mitochondrial apoptotic pathway.

A fresh look at polymicrobial bloodstream infection in cancer patients

Objectives To assess the current incidence, clinical features, risk factors, aetiology, antimicrobial resistance and outcomes of polymicrobial bloodstream infection (PBSI) in patients with cancer. Methods All prospectively collected episodes of PBSI in hospitalised patients were compared with episodes of monomicrobial bloodstream infection (MBSI) between 2006 and 2015. Results We identified 194 (10.2%) episodes of PBSI and 1702 MBSI (89.8%). The presence of cholangitis, biliary stenting, neutropenia, corticosteroids, neutropenic enterocolitis and other abdominal infections were identified as risk factors for PBSI. Overall, Gram-negative organisms were the most frequent aetiology, but Enterococcus spp. were especially frequent causes of Gram-positive PBSI (30.8%). Multidrug-resistant (MDR) organisms were more commonly found in PBSI than in MBSI (20.6% vs 12.9%; p = 0.003). Compared to patients with MBSI, those with PBSI presented with higher early (15% vs 1.4%; p = 0.04) and overall (32% vs 20.9%; p<0.001) case-fatality rates. Risk factors for overall case-fatality were a high-risk MASCC (Multinational Association of Supportive Care in Cancer) index score, corticosteroid use, persistent bacteraemia and septic shock. Conclusions PBSI is a frequent complication in patients with cancer and is responsible for high mortality rates. Physicians should identify patients at risk for PBSI and provide empiric antibiotic therapy that covers the most frequent pathogens involved in these infections, including MDR strains.

The long term follow-up of early stage follicular lymphoma treated with radiotherapy, chemotherapy or combined modality treatment

Local (involved-field or recently involved-site) radiotherapy is the standard therapy in limited-stage follicular lymphoma (FL). We retrospectively analyzed the value of chemotherapy in 130 patients with limited-stage FL (46 treated with radiotherapy alone [RT group], 30 with radiotherapy plus chemotherapy [COMBINED group] and 43 with chemotherapy alone [CHEMO group], 11 were managed with observation). Ninety-six percent of patients responded (RT 98%, COMBINED 100%, CHEMO 91%, p=0.179), and 37% (40/107) of patients in complete response relapsed (RT 42%, COMBINED 27%, CHEMO 41%, p=0.371). Progression-free survival (PFS) and overall survival (OS) probabilities at 10 years were similar in RT, COMBINED and CHEMO patients (PFS 41%, 61% and 39% [p=0.167], and OS 77%, 81% and 72% [p=0.821], respectively), while the COMBINED group showed a trend to better time-to-progression (TTP 43%, 72% and 47% [p=0.055]). On multivariate analysis, only a FLIPI score ≥2 showed a trend to influence PFS (HR 2.1 [95% confidence interval 0.9-4.6], p=0.067), and OS (HR 2.4 [0.9-6.5], p=0.084), while patients treated with radiotherapy plus chemotherapy (COMBINED group) showed a significantly better TTP compared with those receiving only RT (HR 0.3 [0.1-0.8], p=0.024). In our study no benefit was observed in survival with the use of systemic therapy compared with local radiotherapy.

The prohibitin-binding compound fluorizoline induces apoptosis in chronic lymphocytic leukemia cells through the upregulation of NOXA and synergizes with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax

Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In the study herein, the pro-apoptotic effect of fluorizoline was assessed in 34 primary samples from patients with chronic lymphocytic leukemia. Fluorizoline induced apoptosis in chronic lymphocytic leukemia cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespective of patients’ clinical or genetic features, whereas normal T lymphocytes were less sensitive. Fluorizoline increased the protein levels of the pro-apoptotic B-cell lymphoma 2 family member NOXA in chronic lymphocytic leukemia cells. Furthermore, fluorizoline synergized with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax to induce apoptosis. These results suggest that targeting prohibitins could be a new therapeutic strategy for chronic lymphocytic leukemia.

Clinico-biological features, treatment and survival of 457 patients with histological Grades 3A and 1–2 follicular lymphoma mostly treated with immunochemotherapy

Follicular lymphoma (FL) is a non-Hodgkin lymphoma (NHL) of follicle centre B-cells that grow in a follicular pattern. The 2008 World Health Organization (WHO) classification (Swerdlow et al, 2008) divides FL into three major grades: Grade 1 and 2 [<15 centroblasts/high-power field (HPF)] and Grade 3 (>15 centroblasts/HPF). FL Grade 3 is also divided into two types, 3A and 3B; Grade 3A is classified as a preserved maturation of the centrocytes. However, the prognostic value of this grading system remains controversial. Grade 3B FL is currently considered a distinct entity and managed as diffuse large B-cell lymphoma (Horn et al, 2011). It is well known that Grade 1–2, representing 75–90% of all FL cases, has an indolent evolution with a pattern of frequent relapses and is incurable with conventional therapy. However, Grade 3A FL is not yet well defined, with some characteristics of near aggressive lymphoma and others that are almost low-grade (Shustik et al, 2011; Vaidyanathan & Czuczman, 2014). The present study aimed to evaluate initial clinical and biological features, response and outcome of a large cohort of FL Grade 3A and 1–2 patients, most of whom had been treated with immunochemotherapy. Four hundred and fifty-seven patients diagnosed with FL were selected. Primary cutaneous and Grade 3B FL were excluded. In the overall cohort, median follow-up for surviving patients was 5 08 years, with a 10-year overall survival (OS) of 69% [95% confidence interval (CI): 63–75%] and 10-year progression-free survival (PFS) of 38% (95% CI: 32– 44%). Histological grade was based on the current WHO classification, assessed in all patients, and central histological review. Univariate and multivariate analysis was evaluated according to the histological grade, with all main clinical and histological data, prognostic factors, treatment strategies and response. Tumour response was assessed using International Working Group criteria for NHL (Cheson et al, 1999). The main clinical characteristics are summarized in Table I. Comparing the most important clinical differences between Grade 3A and Grade 1–2 FL, less extra nodal involvement was observed in Grade 3A patients, principally due to less bone marrow involvement in this group (Grade 3A, 35%; Grade 1–2, 54%, P = 0 003). This proportion is lower than previously described (Wahlin et al, 2012). Histological analysis did not identify significant differences between BCL2 and CD10 in both groups: 91% and 90% in Grade 3A; 95% and 92% in Grade 1–2, respectively. BCL6 expression was lower in Grade 3A patients: 77/77 (100%) and 54 out of 72 (75%) (P < 0 0001). This data was not previously described; however, this finding did not impact outcome. Ki67 index >50% was evident in Grade 3A compared with Grade 1–2 FL patients: 33/56 (59%) vs. 7/63 (11%) (P < 0 0001). Expression of Ki67 index >50% defined a small group (N = 39) in our cohort with a median survival of 1 5 years (0 7–2 3), regardless of histological subtype. Treatment was heterogeneous in both groups (Table I). Patients with FL Grade 3A were more frequently treated with anthracyclines and rituximab, and received less fludarabine, A trend towards a high complete response rate was observed in the Grade 3A FL group (Table SI). In univariate and multivariate analysis, the most important variables predicting response in FL Grade 3A patients was the FL International Prognostic Index (FLIPI) score (P = 0 009) and, included FLIPI score (P < 0 0001) and b2microglobulin (P = 0 041) for the Grade 1–2 group (Table SII). No significant differences in outcome (PFS and OS) were observed between Grades 1–2 and 3A (Fig 1). Of 270 patients that achieved CR, 121 relapsed: 21 (35%) FL Grade 3A patients and 100 (46%) FL Grade 1–2 patients (P = 0 126). At the time of this analysis, 24 (27 3%) and 91 (24 7%) FL Grade 3A and 1–2 patients, respectively, had died, mostly due to lymphoma progression. As expected, FLIPI score still remained an important prognostic factor for OS in both groups (Grade 3A, P = 0 050; Grade 1–2, P = 0 045). Univariate and Cox multivariate analysis of survival in both groups is shown in Table SIII. In our series, 95% and 70% of the Grade 3A and Grade 1–2 patients, respectively, received upfront anthracyclines (P < 0 0001). When only patients treated with anthracyclines were analysed, no differences in terms of OS and PFS were observed between the Grade 3A and Grade 1–2 cohorts (Fig S1), or when analysed for each particular group (Table SIII), and was in agreement with previous reports (Chau et al, 2003; Ganti et al, 2006). This report describes the largest number of FL patients treated with immunochemotherapy published to date. Upfront and cumulative rituximab treatment in Grade 3A and 1–2 FL patients were: 68% vs. 47% and 77% vs. 63%, respectively (P < 0 0001 and P = 0 032). OS probabilities were identical in Grades 1–2 and 3A patients treated with upfront and cumulative rituximab (Fig S2 and S3), and were the same in terms of PFS in upfront rituximab patients (Fig S2). However, PFS showed a non-significant trend for