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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may complicate hematologic malignancies. HLH and malignancies have common clinical features, and HLH diagnostic criteria (HLH-2004/Hscore) were not validated in this specific population. We describe a case of a 72-year-old patient with a history of chronic lymphocytic leukemia stable for over 10 years who presented with fever and cytopenia. After excluding infectious etiologies and the progression of her disease, HLH was diagnosed. The patient was treated with etoposide, dexamethasone, intravenous immunoglobulin, and rituximab. Despite initial clinical improvement, the patient deteriorated and developed pulmonary aspergillosis and CNS involvement that reflected uncontrolled HLH. The patient died 45 days after her presentation. An unusual feature of this case was that HLH was not triggered by infection, disease transformation, or treatment. This case emphasizes the challenges of differentiating the development of overwhelming HLH from other complications associated with hematologic malignancy.

Background Major advances in the treatment of patients with hairy cell leukemia (HCL) have been made following the introduction of purine analogues. The major significant short-term toxicity of cladribine therapy are neutropenia and neutropenic fever (NF) which may be life-threatening. Aim In this retrospective study, we compared the incidence and duration of neutropenia and hospitalization in patients with HCL treated with cladribine followed by peg-filgrastim as primary prophylaxis versus daily filgrastim given “on demand” according to absolute neutrophil count (ANC). Methods Medical records of patients with HCL diagnosed and followed in 12 medical centers in Israel during 1985–2015 were examined for details of disease at diagnosis. The efficacy of peg-filgrastim and filgrastim was assessed by evaluating the incidence of neutropenia (ANC 9 ]/L), number and length of hospitalizations, and number of days from the last day of therapy to recovery of ANC to >1.0 × 10 [ 9 ]/L. Results The study population included 202 patients with HCL, 159 of whom (80.7%) were treated with cladribine; 78 patients (49%) required hospitalization for the administration of broad-spectrum antibiotics due to NF. Twenty-eight (19%) patients were treated with peg-filgrastim as primary prophylaxis, while 74 (64%) received filgrastim “on demand” due to neutropenia. Median length of hospitalization, and nadir duration were 8 and 18 days respectively (p = 0.71, p = 0.44). Conclusions Infectious complications post-cladribine treatment remain high. No difference was found in terms of incidence of NF, number of febrile days, and nadir duration in patients receiving primary peg-filgrastim prophylaxis compared to filgrastim given on demand. Both approaches are justifiable, and the choice remains at the physician’s discretion.

BACKGROUND Chronic lymphocytic leukemia (CLL) is frequently accompanied by immune dysregulation. AIMS In this multicenter prospective study, we investigated whether heavy + light chains (HLC: IgGκ, IgGλ, IgAκ, IgAκ, IgMκ, IgMλ) and IgG subclasses (IgG1, IgG2, IgG3, and IgG4) could be used as novel prognostic markers of immunoparesis in 105 treatment-naive patients with CLL. RESULTS Heavy + light chains immunoparesis of ≥1, ≥2, and ≥3 isotypes was evident in 74 (70%), 58 (55%), and 36 (34%) patients, respectively. Severe HLC immunoparesis was identified in 40 (38%) patients. Of the IgG subclasses, IgG1 and IgG2 were most frequently suppressed, affecting 46 (44%) and 36 (34%) patients, respectively; 63 (60%) patients had low levels of at least one IgG subclass. In multivariate analysis, severe HLC immunoparesis (hazard ratio [HR]: 36.5; P = .010) and ΣFLC ≥ 70 mg/L (HR: 13.2; P = .004) were the only factors independently associated with time to first treatment (TTFT). A risk model including these variables identified patients with 0, 1, and 2 risk factors and significantly different TTFT (P

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. The therapeutic approach to CLL includes chemotherapeutic regimens and immunotherapy. Complement-mediated cytotoxicity, which is one of the mechanisms activated by the therapeutic monoclonal antibodies, depends on the availability and activity of the complement (C) system. The aim was to study the structure of circulating C components and evaluate the importance of C5 structural integrity for C activity in CLL patients. Blood samples were collected from 40 naïve CLL patients and 15 normal controls (NC). The Western blot analysis showed abnormal C5 pattern in some CLL patients, while patterns of C3 and C4 were similar in all subjects. Levels of the C activation markers sC5b-9 and C5a were quantified before and after activation via the classical (CP) and alternative (AP) pathways. In patients with abnormal C5, basal levels of sC5b-9 and C5a were increased while activities of the CP and of the CP C5-convertase, the immediate C5-upstream complex, were decreased compared to NC and to patients with normal C5. The data indicate a link between CP activation and apparent C5 alterations in CLL. This provides a potential prognostic tool that may personalize therapy by identifying a sub-group of CLL patients who display an abnormal C5 pattern, high basal levels of sC5b-9 and C5a, and impaired CP activity, and are likely to be less responsive to immunotherapy due to compromised CP activity.

The immunotherapy treatments offered for Chronic lymphocytic leukemia (CLL) activate various cellular and biochemical mechanisms, including the complement system. Recently it was shown that the classical complement pathway (CP) in CLL patients is persistently activated at a low level through (Michelis et al. PlosOne, 2019), and that the mechanism of chronic CP activation involves the formation of IgG-hexamers (Michelis et al. PlosOne, 2020). According to recent studies, formation of ordered IgG-hexamers occurs on cell surfaces via specific interactions between Fc regions of the IgG monomers, which occur only after antigen binding. The study investigated the formation of IgG-hexamers in CLL patients and normal controls (NC), their ability to activate complement, their incidence as cell-free and cell-bound forms and the identity of the antigen causing their formation. Sera from 30 patients and NC were used for separation of IgG-hexamers. The obtained IgG-hexamers were measure and used for assessment of CP activity. For evaluation of the presence of IgG-hexamers on blood cells, whole blood samples were stained and assessed by flow cytometry. Serum levels of IgG-hexamers were higher in patients compared to NC. Also, they activated the complement system to a higher extent in patients than in NC. Alpha 2 macroglobulin (A2M) was recognized as the antigen causing the hexamerization of IgG, and was found to be part of the hexamer structure by mass spectrometry, Western blot and flow cytometry analysis. The presence of A2M-IgG-hexamers on B-cells suggests that it may be formed on B cells surface and then be detached to become cell-free. Alternatively, it may form in the plasma and then attach to the surface of the cells. The exact course of A2M-IgG-hexamers formation in CLL should be further studied. The results in this study may be useful for improvement of current immunotherapy regimens. Disclosures Tadmor: Neopharm: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Aviv:Abbvie: Honoraria.

Background/aim In this retrospective study, we summarized the national Israeli experience with hairy cell leukemia (HCL) in a large cohort of patients with a long follow-up. Patients and methods Demographic data, and relevant laboratory and clinical parameters were analyzed, emphasizing the outcome after first-line treatment with cladribine. Results Data on 203 patients was collected from 12 medical centers during 1985-2015. Mean and median follow-up were 7.5 years and 5.18 years (interquartile range=0.1-40 years), and 5- and 10-year survival were 96% and 90.62%, respectively. The median age of diagnosis was 55.5 years for Jews and 49 years for Arabs (p=0.021), and most patients were males (81.77%); 52.2% were Ashkenazi Jews, 36.1% Sephardic Jews and 11.7% were Arab, Druze or other ethnicity. Cladribine was given to 159 patients (80.7%%) and most (62%) received intravenous (i.v.) and 38% received subcutaneous (s.c.) therapy. Overall survival and time to next treatment were not significantly different between the two schedules (i.v., s.c.). In univariate analysis of a variety of factors, only age >65 years had a negative impact on outcome, with shorter overall survival. It is of interest that Arab patients with HCL were diagnosed at an earlier age, but had a similar clinical course and outcome to both Ashkenazi and Sephardic Jews.

Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. The fludarabine, cyclophosphamide, and rituximab (FCR) regimen is considered the treatment of choice for young fit patients with CLL; however, this combination is toxic for older patients. At the time this study was first planned and initiated, there was no standard chemo-immunotherapy regimen regarded as standard therapy for the less fit elderly patient with CLL. Here, we conducted a single-arm, phase II trial to examine the efficacy and safety of lower-dose fludarabine and cyclophosphamide combined with a standard dose of rituximab (LD-FCR) in elderly patients with previously untreated CLL. Forty patients received LD-FCR and were included in the efficacy analysis. Two patients treated with FC alone were only included in the safety analysis. The median age was 72.7 years (range, 65.0 to 85.0). The overall response and complete response rates were 67.5% and 42.5%, respectively. Median progression-free survival (PFS) was 35.5 months (95% CI, 29.27-41.67). Two patients (4.8%) died during the study period. Hematological toxicities and infections were the most common complications encountered; grade 3 to 4 treatment-related neutropenia occurred in 20 (47.6%) patients. During the entire study follow-up, 26 patients (61.9%) had all grades of infection including six (14.3%) with neutropenic fever and eight (19%) with grade 3 to 4 non-neutropenic infections. In conclusion, LD-FCR is an effective and relatively safe regimen for previously untreated patients with CLL. It has the advantage of being both "time and cost limited" and, even in the era of novel agents, can still be considered when planning treatment for elderly patients without high-risk biomarkers. However, recent results in fit elderly patients using the combination of bendamustine and rituximab which have achieved longer PFS with good safety profile must be taken into consideration in this regard.

Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. Despite the development of novel agents and new monoclonal antibodies, FCR still remains the combination chemoimmunotherapy of choice for fit patients with CLL, yielding the longest durations of remission. When this study was first started, no established chemo-immunotherapy regimen was unanimously regarded as standard therapy for less fit elderly patients with CLL; this category of patients had clearly been underrepresented in clinical trials utilizing chemo - or chemo-immunotherapy. Patients and Methods We conducted a single arm, phase II trial to assess the efficacy and toxicity of low dose fludarabine and cyclophosphamide in combination with a regular dose of rituximab (FCR-LITE) in elderly patients with therapy naïve CLL. Our intention was to deliver 6 courses of Fludarabine which was given intravenously (IV) at 12.5 mg/m2/day together with IV cyclophosphamide 150 mg/m2/day for 3 consecutive days. IV rituximab was administered on day 0 of cycle 1 at a dose of 375 mg/m2, and at 500 mg/m2 on day 1 of cycles 2-6. Categorical variables were compared in patients with and without CR using chi-square test or Fisher's exact test and continuous variables were also compared using Mann Whitney test. Duration of follow-up was recorded using reverse censoring method. Kaplan Meier curve was used to establish PFS during clinical follow-up. All statistical tests were two sided. P Results Forty patients treated with FCR-LITE were included in the efficacy analysis. The median age of the entire cohort was 72.7 years (range, 65.0 to 85.0), and 69% were male. The mean number of treatment cycles was 5.1 (range 1-6). The overall response rate was 67.5% (95% CI, 50.9%-81.4%); 17 patients (42.5%) achieved CR and 10 (25.0%) PR. Median PFS was 35.5 months (95% CI, 29.27-41.67). Two patients (4.8%) died during the study period. Reduced cumulative doses of FCR and fewer courses of treatment were both associated with lower CR rate. Hematological toxicities were the most common side effects encountered; grade-3/4 neutropenia occurred in twenty (47.6%) patients, only six (14.3%) developed neutropenic fever. Positive direct antiglobulin test (DAT), was seen in 11 patients but none of them developed autoimmune hemolytic anemia (AIHA) during treatment; two patients (4.8%) progressed to Richter's transformation and two (4.8%) had second malignancies (lung and metastatic colon carcinoma). Conclusion FCR-LITE is effective and safe for treating elderly patients with therapy-naïve CLL. It has the advantage of being both time and cost effective. In an era of novel agents, it can still be considered as suitable frontline treatment for fit elderly patients with CLL. This research was supported by roche pharmaceuticals Table. Table. Disclosures Tadmor: ABBVIE: Consultancy; ROCHE: Research Funding; NOVARTIS: Consultancy; JNJ: Consultancy; PFIEZER: Consultancy. Herishanu:JNJ: Consultancy; ABBVIE: Consultancy; ROCHE: Research Funding. Bairey:ROCHE: Research Funding; AbbVie: Consultancy; Jansen: Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Rahimi-Levene:ABBVIE: Consultancy. Fineman:ABBVIE: Consultancy; JNJ: Consultancy. Ruchlemer:JNJ: Consultancy; ABBVIE: Consultancy. Shvidel:JNJ: Consultancy; ROCHE: Consultancy, Research Funding; ABBVIE: Consultancy, Research Funding. Polliack:ABBVIE: Consultancy; ROCHE: Research Funding.

Introduction: Chronic Lymphocytic Leukemia (CLL) is frequently accompanied by immune dysregulation. Hypogammaglobulinemia is one of the most important immune defects encountered, and all three classes of immunoglobulins (IgG, A and M) can be involved. Recently, novel heavy+light chain (HLC) immunoassays have become available that quantify the light chain types of each immunoglobulin class (e.g. IgGk and IgGl). These assays are measured in pairs and provide information on the isotype produced by a tumour (the "involved" HLC), the non-clonal ("uninvolved") HLC, and the ratio (e.g. IgGk/IgGl) - which indicates monoclonality. HLC assays have been shown to improve monitoring of plasma cell dyscrasias, but their role in CLL is yet to be studied. Methods This is a multi-center study performed in collaboration with the Israeli CLL Study Group and involved 10 medical centers. The cohort included 122 patients with CLL and 26 healthy controls. Baseline was defined as the time the blood sample was taken. Serum samples were analyzed for levels of IgG subclasses (IgG1, IgG2, IgG3, IgG4), heavy+light chains (HLC) (IgGκ, IgGλ, IgAκ, IgAλ, IgMκ or IgMλ) and free light chains (sFLC). HLC-pair suppression was defined as an abnormal HLC ratio and uninvolved HLC levels below the normal reference range (i.e. in g/L: IgGκ HLC immunoparesis was defined as HLC isotype levels below the normal reference range, regardless of HLC ratio (i.e. HLC immunoparesis of at least 1 isotype indicates at least one of IgGκ, IgGλ, IgAκ, IgAλ, IgMκ or IgMλ below the normal reference range). Severe HLC-pair suppression or severe HLC immunoparesis was defined as a concentration of the uninvolved HLC or any HLC isotype that is suppressed by >50% below the normal reference range. The association of variables with time to first treatment (TTT) was performed with Cox proportional hazard model. Results Current analysis was performed on 105 CLL patients who had complete data available; median age was 68 years, 64% were males and Binet stage A, B, C, were 80%, 18.1% and 1.9% respectively. Median time from diagnosis to baseline measurements was 27 months (range 0-328 months). An abnormal sFLC ratio was identified in 70% (73/105) patients and summated k and λ concentrations (SFLC) were ≥70 mg/L in 18% of cases. An abnormal HLC ratio was present in 32% (34/105) patients, and 21% had HLC pair suppression of any 1 HLC isotype. HLC immunoparesis of 1, ≥2 and ≥3 isotypes was observed in 74 (70%), 58 (55%) and 36 (34%) of patients, respectively, with severe HLC immunoparesis identified in 40 patients (38%). Patients with IgG2 suppression were more frequently hospitalized due to infection with an Odds Ratio of 3.826 (p=0.031). In multivariate analysis, SFLC ≥70 mg/L and severe HLC immunoparesis were independently associated with TTT (HR 15.3, p Conclusions The findings presented here demonstrate that there is considerable potential for the use of HLC and FLC immunoassays to provide prognostic information in CLL. Figure 1. Figure 1. Disclosures Tadmor: PFIEZER: Consultancy; JNJ: Consultancy; ABBVIE: Consultancy; NOVARTIS: Consultancy; ROCHE: Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Herishanu:ROCHE: Research Funding; JNJ: Consultancy; ABBVIE: Consultancy. Shvidel:ROCHE: Consultancy, Research Funding; ABBVIE: Consultancy, Research Funding; JNJ: Consultancy. Rahimi-Levene:ABBVIE: Consultancy. Ruchlemer:ABBVIE: Consultancy; JNJ: Consultancy. Fogl:The Binding Site Group Ltd: Employment. Polliack:ROCHE: Research Funding; ABBVIE: Consultancy. Magal:The Binding Site: Employment. Townsend:The Binding Site Group Ltd: Employment.

Background: The Israel National Cancer Registry (INCR) is a population based, national passive tumor registry established in 1960. Reporting by hospitals, laboratories, and other providers has been mandatory in Israel since 1982 and most cancer cases are registered on the basis of pathology reports and hospital records. In some hematopoietic malignancies where the diagnosis was not based on tissue pathology and patients initially received no inpatient treatment, cases may not have been reported to the registry, or reporting to the INCR may have been delayed, resulting in an underestimation of the true burden of disease. One diagnosis for which there is particular concern in this regard is CLL/SLL and here we used active surveillance to estimate the true incidence of CLL/SLL in Israel. Here we present the interim results Methods: We attempted to estimate the incidence of CLL in Israel more accurately,recognizing the fact that the exact incidence may never be known. The Israel Chronic Lymphocytic Leukemia Study Group, working with the Israel Center for Disease Control of the Ministry of Health, actively documented new cases of CLL/SLL in Israel for calendar years 2011 and 2012. All flow cytometry laboratories in Israel provided lists of patients with B cell clones. Israeli hematologists diagnosing CLL were asked to verify which of the B cell clones indicated a diagnosis of CLL, SLL, PLL or MBL and to fill out an internet-based reporting form. Diagnoses based on flow cytometry were verified by medical record review. Cases identified through active surveillance were pooled with cases known to INCR in order to estimate the true annual incidence of CLL/SLL and assess the completeness of the INCR data. Results: We identified 432 and 396 CLL/SLL cases for 2011 and 2012, respectively of whom 57.4% were males. The average age was 68.8. The corresponding age-adjusted[1]incidence rates per 100,000 (ASR) were 4.26 for 2011 and 3.79 for 2012. In comparison, the INCR registered 295 new CLL cases in 2011 (ASR=2.78) and 232 in 2012 (ASR=2.19), 54.5% of them males. The average age at diagnosis was 69.9. These data indicate a gap between true and reported incidence (1.48 and 1.60/100,000 in 2011 and 2012, respectively). However, it should be noted that the INCR will be fully updated for 2012 only by the beginning of 2015. Of active surveillance cases, 157 (2011) and 152 (2012) were registered in the INCR. Most cases missing in the INCR were diagnosed based on flow cytometry, peripheral blood samples and FISH (85.9% in 2011, 89.8% in 2012) without histo-pathological confirmation. Of the CLL/SLL cases existing in the INCR dataset for 2011-12 but not detected by active surveillance (138 in 2011; 80 in 2012), most (76.8% in 2011, 63.8% in 2012) had been diagnosed earlier and the remainder were coded as diagnoses other than CLL/SLL. Omitting these cases from the INCR dataset substantially increased the observed gaps in the true and the registered annual incidence of CLL/SLL (from 1.48 to 2.80 per 100,000 in 2011 and from 1.60 to 2.37 per 100,000 in 2012). Conclusions: The true incidence of CLL is unknown, but it is clear that there is under reporting to cancer registries. Completeness of CLL/SLL data requires accurate reporting of cases by hematologists and other care providers in the community. In Israel, this issue has been addressed by publishing updated guidelines for mandatory reporting stressing the requirement for reporting of hematologic malignancies. [1] Age-adjustment made on the basis of the world standard population Disclosures Ruchlemer: Roche: Research Funding.