Ariel Aviv

Merkel cell carcinoma, chronic lymphocytic leukemia and other lymphoproliferative disorders: an old bond with possible new viral ties

Merkel cell carcinoma (MCC) is a rare and aggressive skin tumor. The link between tumorigenesis and immunosuppression is well known and the increased prevalence of MCC in human immunodeficiency virus carriers and organ transplant recipients and in patients with hemato-oncological neoplasias is now well recognized over the past decade. In this respect, chronic lymphocytic leukemia (CLL) seems to be the most frequent neoplasia associated with the development of MCC. Very recently, a newly described virus, the Merkel cell polyomavirus, was found in ∼80% of MCC tumor samples and is in fact the first member of the polyomavirus family to be associated with human tumors. The virus appears to play a role in the pathogenesis of MCC and may constitute the missing link between immunosuppression and the development of MCC. This review summarizes the current knowledge relating to MCC and its pathogenesis, stressing the link with hematologic neoplasias in general and to CLL in particular. We describe the permissive immunologic environment, which enables the virus-containing tumor cells to survive and proliferate in disorders like CLL. More studies are still needed to confirm this appealing theory in a more convincing manner.

Primary diffuse large B-cell lymphoma of the breast: looking at pathogenesis, clinical issues and therapeutic options

Primary breast lymphoma is a rare form of non-Hodgkin lymphoma with some distinct clinical features. The most common histopathological type is diffuse large B-cell lymphoma (DLBCL), but other less frequent subtypes are also encountered. In this review, we describe the characteristics of primary breast DLBCL, with emphasis on pathogenesis, staging, risk stratification and prognosis. In addition, key issues regarding therapy and various available therapeutic modalities are addressed, as well as the role of rituximab in therapy and whether central nervous system prophylaxis is still routinely required. There are very few prospective clinical studies addressing therapy, and available data rely mostly on retrospective case series involving small numbers of patients. Our conclusions and proposed recommendations are therefore not offered as formal guidelines. This review attempts to represent an unbiased analysis of the published data and is intended as a useful aid for clinicians treating this uncommon type of extra nodal lymphoma.

Predicting infections in high‐risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: Aretrospective multicenter study

Hypomethylating agents have become the standard therapy for patients with high‐risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA‐treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high‐risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29–92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 × 109/L and neutrophil count below 0.5 × 109/L were predictive of the risk of infection during the first two cycles of therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at high risk for infections and infection prophylaxis may be considered. Am. J. Hematol. 88:130–134, 2013.

Increased incidence of chronic lymphocytic leukaemia and lymphomas in patients with Merkel cell carcinoma – a population based study of 335 cases with neuroendocrine skin tumour

Merkel cell carcinoma (MCC) is a rare aggressive skin tumour that appears to be associated with a large number of other tumours. We collected all reported cases in Israel and estimated its association with other tumours, including haematological malignancies. The population based Israel Cancer Registry identified 335 patients with MCC diagnosed between1989 and 2010. Ninety‐seven percent were in the Jewish population; median age at diagnosis for Jewish patients was 73·4 and 55·6 years for the Arab population. Other associated malignancies were encountered in 92 patients (27·4%) with MCC (90 Jews, two Arabs). Of the Jewish cases, 66 presented with an associated malignancy before, and 24 after, the diagnosis of MCC. Solid tumours were not significantly increased among patients with MCC. Thirty‐one of these associated cancers (34·4%) were haemato‐oncological malignancies, 24 were detected before and seven after the diagnosis of MCC. The standardized incidence ratio (SIR) for haematological malignancy was 3·67 for males and 3·62 for females, and the most frequent haemato‐oncological neoplasias recorded were chronic lymphocytic leukaemia (45%) and lymphomas (29%). Although MCC is rare, clinicians should be aware of the possible association with B‐cell lymphoproliferative disorders when evaluating patients with neuroendocrine skin tumours.

Richter's transformation to diffuse large B-cell lymphoma: A retrospective study reporting clinical data, outcome, and the benefit of adding rituximab to chemotherapy, from the Israeli CLL Study Group

Richters syndrome (RS) is the rare development of an aggressive lymphoid malignancy in a patient with pre‐existing chronic lymphocytic leukemia (CLL). Data on RS is sparse and mostly derived from case reports or small series of patients and only a few larger cohorts have been published. The purpose of this large retrospective study was to summarize our national experience with RS in CLL, examine possible risk factors, and analyze relevant demographic, laboratory and clinical parameters, including results of therapy and outcome. We first evaluated data obtained from 119 patients with RS diagnosed during 1971–2010 from 12 medical centers in Israel. The final cohort summarized consisted of 81 patients with RS who developed only diffuse large B‐cell lymphoma (DLBCL) after exclusion all cases with insufficient data and those who were not DLBCL. Median overall survival from time of diagnosis of RS was 8 months; after applying the Richter score, patients could be stratified into three prognostic groups, while all other clinical and laboratory parameters evaluated had no prognostic significance. Prior therapy for CLL had no impact on RS survival (P = 0.8) and patients with therapy “naïve” RS and those who had already received chemotherapy prior to developing RS, had the same survival. The addition of rituximab to chemotherapy for RS improved 2 years overall survival from 19% in the chemotherapy alone arm to 42% (P value of 0.001). Although prognosis of patients with RS remains dismal, this retrospective observation provides support for the use of chemo‐immunotherapy in DLBCL‐RS. Am. J. Hematol. 89:E218–E222, 2014.

Higher Infection Rate After 7- Compared With 5-Day Cycle of Azacitidine in Patients With Higher-Risk Myelodysplastic Syndrome

INTRODUCTION Azacitidine (AZA) dose reduction is a common practice in cytopenic patients. However, a correlation between AZA dose and infection complications has never been studied. PATIENTS AND METHODS Higher-risk patients with myelodysplastic syndrome or acute myeloid leukemia treated with AZA in 18 Israeli hospitals between the years 2008 and 2011 were included in a former national survey. To reveal the effect of AZA dosage on infection risk we limited our analysis to the infection rate after the first AZA dose alone. We excluded subsequent cycles of AZA from the analysis, because infectious events during these cycles might be related to other cofactors such as disease response to AZA therapy. RESULTS After the first AZA cycle, infectious events were more frequent after doses of 75 mg/m(2) for 7 days than 75 mg/m(2) for 5 days (36/106 [34%] and 10/67 [14.9%], respectively; P = .008), regardless of the patients age. Of the 46 recorded infectious events, the causative pathogen was identified as bacterial in 25 (54.3%) and as viral or fungal in 2 (4.3%) and 2 (4.3%) cases, respectively. No pathogen was identified in 17 (37%) cases. Infections were significantly more prevalent among patients who presented with platelet counts < 20,000 (43.6% vs. 23.6%; P = .012) and poor risk cytogenetics (40.7% vs. 19.8%; P = .008). CONCLUSION Reduction of AZA dose might decrease infection rate and therefore should be considered in patients with high infection risk.

Infections associated with bendamustine containing regimens in hematological patients: a retrospective multi-center study

A multi-center retrospective analysis of a cohort of patients in Israel treated with any bendamustine containing regimen between 2010–2014 was performed in order to determine the incidence and predictors for infection. The Kaplan Meier Model, employing log rank analysis, was used to assess time-to-infection. The Cox Proportional Hazards model was used to analyze multivariate effects of risk and 234 patients were included in the analysis. One hundred and nine (46.6%) developed at least one infection and 33.76% had severe infections. Seventy-six (41.5%) developed bacterial infection, nine (3.8%) fungal infection and 26 (11.5%) had viral infections. Factors significantly associated with time to infection on multivariable analysis were: bendamustine-combinations [hazard ratio (HR) = 0.589 (95% CI = 0.374–0.926), p = 0.022], Hb level [HR = 0.791 (95% CI = 0.716–0.875), p < 0.0001] and ischemic heart disease [HR = 1.828 (95% CI = 1.165–2.868), p = 0.009]. Infections were associated with a higher mortality and hospitalization rate.

Absolute Monocyte Count and Lymphocyte-Monocyte Ratio Predict Outcome in Nodular Sclerosis Hodgkin Lymphoma: Evaluation Based on Data From 1450 Patients

OBJECTIVE To verify whether absolute monocyte count (AMC) and lymphocyte- monocyte ratio (LMR) at diagnosis are valid prognostic parameters in classical Hodgkin lymphoma (cHL). PATIENTS AND METHODS Data were collected from 1450 patients with cHL treated in Israel and Italy from January 1, 1988, through December 31, 2007. RESULTS The median age of the patients was 33 years (range, 17-72 years), and 70% (1017) of the patients had nodular sclerosis (NS); the median follow-up duration was 87 months. The best cutoff value for AMC was 750 cells/mm(3), and the best ratio for LMR was 2.1. The adverse prognostic impact of an AMC of more than 750 cells/mm(3) was confirmed for the entire cohort, and its clinical significance was particularly evident in patients with NS histology. The progression-free survival (PFS) at 10 years for an AMC of more than 750 cells/mm(3) was 65% (56%-72%), and the PFS at 10 years for an AMC of 750 cells/mm(3) or less was 81% (76%-84%; P<.001). The overall survival (OS) at 10 years for an AMC of more than 750 cells/mm(3) was 78% (70%-85%), and the OS at 10 years for an AMC of 750 cells/mm(3) or less was 88% (84%-90%; P=.01). In multivariate analysis, both AMC and LMR maintained prognostic significance for PFS (hazard ratio [HR], 1.54, P=.006, and HR, 1.50, P=.006) after adjusting for the international prognostic score, whereas the impact on OS was confirmed (HR, 1.56; P=.04) only in patients with NS and an AMC of more than 750 cells/mm(3). CONCLUSION This study confirms that AMC has prognostic value in cHL that is particularly significant in patients with NS subtype histology. This finding links the known impact of macrophages and monocytes in Hodgkin lymphoma with routine clinical practice.

Significance of bone marrow reticulin fibrosis in chronic lymphocytic leukemia at diagnosis: a study of 176 patients with prognostic implications.

Bone marrow (BM) biopsies from patients with chronic lymphocytic leukemia (CLL) may show reticulin fibrosis at diagnosis, but its significance remains unclear. This study sought to assess the prognostic impact of BM reticulin fibrosis in patients with previously untreated CLL.

Neutrophil-lymphocyte ratio at diagnosis is an independent prognostic factor in patients with nodular sclerosis Hodgkin lymphoma: results of a large multicenter study involving 990 patients

Several studies have demonstrated the prognostic value of neutrophil‐lymphocyte ratio (NLR) in patients with solid tumors and non–Hodgkin lymphoma. In contrast, there is only sparse data on its prognostic role in patients with classical Hodgkin lymphoma (cHL). The aim of our study was to establish whether NLR could serve as an independent prognostic factor in a cohort of 990 patients with nodular sclerosis (NS)‐cHL. After analysis of the log hazard ratio (HR) as a function of NLR, we chose the value 6 as cutoff. Patients with NLR >6 had a worse progression‐free survival and overall survival compared to those with NLR ≤6; 84% vs 75% and 92% vs 88%, at 5 years, with an HR of 1.65 and 1.82, respectively. Multivariate analysis showed that the risk remained high with HR 1.44 and HR 1.54 in progression‐free survival and overall survival, respectively. In summary, our study shows that NLR is a robust and independent prognostic parameter in NS‐cHL, both in early and advanced disease. It is inexpensive and simple to apply. Thus, we conclude that NLR, possibly in combination with the international prognostic score and absolute monocyte count, is a useful guide for physicians treating NS‐cHL patients.