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Despite the increase in the number of prognostic models currently available for evaluating patients with chronic lymphocytic leukemia (CLL), their current application and utilization in clinical practice in the era of targeted agents is unclear. A critical reappraisal of recently developed prognostic models is presented in this review. The underlying CLL's genetic instability and changes in the host's health and comorbidities can all contribute to the acquisition of additional risk factors for adverse outcomes during the course of the disease. Therefore, available risk models solely based on pretreatment variables only partially predict patients' clinical outcome. A dynamic prognostic model that takes into account changes in the risk profile over time could indeed be useful in routine clinical practice. The next generation of risk assessment models should incorporate post-treatment and response biomarkers such as minimal residual disease. Finally, recent advances in the field of machine learning present novel opportunities to generate models capable of providing an individualized estimation of clinical outcomes in CLL. However, in the era of improved prognostic models, it is important to remember that these indices should supplement but not replace clinical expertise and medical decision-making.

A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

Autoimmune manifestations are known to occur in patients with chronic lymphocytic leukemia (CLL) and of these hemolytic anemia and immune thrombocytopenia are the most well recognized. Autoimmunity may also be triggered by some of the therapeutic agents used like purine analoges and these events may sometimes be severe and even fatal. Non-hematological autoimmune stigmata occur far less frequently and are rarely encountered. Here we report a 59 year-old-woman, with CLL, who complained of recurrent headache starting 1 month after completing 6 cycles of fludarabine, cyclophosphamide, and rituximab combination therapy. Computed tomography scan of the brain showed a contrast enhancing lesion of 1 cm in diameter, with surrounding edema in the right frontal lobe. Brain MRI revealed ring enhancing lesions in the right frontal lobe and some additional small lesions in the left parietal lobe. Brain biopsy showed an inflammatory demyelinating lesion, not associated with JC virus. The patient subsequently improved after steroid therapy. Currently, after 2 years of follow-up, she remains in complete hematologic remission, has no neurological deficits, and is carefully followed by a team of neurologists and hematologists. Treating physicians should be aware of this rare autoimmune inflammatory demyelinating lesion which can occur in patients with CLL during the course of treatment and that may be linked to treatment with purine analogues like fludarabine.

Skeletal involvement is a rare complication of hairy cell leukemia (HCL) with an incidence of approximately 3%. Bone lesions are commonly lytic, and the most common sites of involvement are the femoral head and neck. Skeletal involvement is typically associated with high tumor burden and bone marrow infiltration. However, isolated cases of skeletal disease without splenomegaly or bone marrow involvement are occasionally reported. This review focuses on skeletal lesions in HCL, particularly the pathogenesis, clinical symptoms, diagnostic methods, and treatment approach. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skeletal symptoms, bone involvement was conducted via PubMed. Publications from January 1970 to May 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles.

In immunocompetent people, the mRNA vaccines BNT162b2 and mRNA-1273 have been shown to be safe and effective against coronavirus disease of 2019 (COVID-19). However, results of cohort studies and meta-analyses have indicated that the degree of humoral response to SARS-CoV-2 vaccines in patients with chronic lymphocytic leukemia (CLL) appears to be lower than that observed in the general population. These inadequate responses are mainly related to the disease itself and to the immunosuppressive effect of therapies administered. In the specific context of CLL, enrolling patients with sub-optimal vaccine-response in pivotal vaccine trials could be considered as an appropriate approach to improve response to the COVID-19 vaccine. These clinical trials should also address the issues of regularity and timing of vaccine booster doses or re-vaccinations, especially in patients undergoing therapy with pathway-targeting agents and anti-CD20 monoclonal antibodies. However, since hypogammaglobulinemia is a serious consequence of CLL, patients who do not have a detectable antibody response should be natural candidates for preventive antibody therapy.

Patients with chronic lymphocytic leukemia (CLL) have an impaired antibody response to coronavirus disease 2019 (COVID-19) vaccination. Here, we evaluated the antibody response to a third BNT162b2 mRNA vaccine in patients with CLL/small lymphocytic lymphoma (SLL) who failed to achieve a humoral response after standard 2-dose vaccination regimen. Anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies were measured 3 weeks after administration of the third dose. In 172 patients with CLL, the antibody response rate was 23.8%. Response rate among actively treated patients (12.0%; n = 12/100) was lower compared with treatment-naïve patients (40.0%; n = 16/40; OR = 4.9, 95% CI 1.9-12.9; P < .001) and patients off-therapy (40.6%; n = 13/32; OR = 5.0, 95% CI 1.8-14.1; P < .001), (P < .001). In patients actively treated with Bruton’s tyrosine kinase (BTK) inhibitors or venetoclax ± anti-CD20 antibody, response rates were extremely low (15.3%, n = 9/59, and 7.7%, n = 3/39, respectively). Only 1 of the 28 patients (3.6%) treated with anti-CD20 antibodies

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.

Patients with chronic lymphocytic leukemia (CLL) have a suboptimal humoral response to vaccination. Recently, BNT162b2, an mRNA COVID-19 vaccine with a high efficacy of 95% in immunocompetent individuals, was introduced. We investigated the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with CLL from nine medical centers in Israel, Overall 400 patients were included, of whom 373 were found to be eligible for the analysis of antibody response. The vaccine appeared to be safe and only grade 1-2 adverse events were seen in 50% of the patients. Following the second dose, an antibody response was detected in 43% of the cohort. Among these CLL patients, 61% of the treatment-na ve patients responded to the vaccine, while responses developed in only 18% of those with ongoing disease, 37% of those previously treated with a BTK inhibitor and 5% of those recently given an anti-CD20 antibody. Among patients treated with BCL2 as monotherapy or in combination with anti-CD20, 62% and 14%, respectively, developed an immune response. There was a high concordance between neutralizing antibodies and positive serological response to spike protein. Based on our findings we developed a simple seven-factor score including timing of any treatment with anti-CD20, age, treatment status, and IgG, IgA, IgM and hemoglobin levels. The sum of all the above parameters can serve as a possible estimate to predict whether a given CLL patient will develop sufficient antibodies. In conclusion, the BNT162b2 mRNA COVID-19 vaccine was found to be safe in patients with CLL, but its efficacy is limited, particularly in treated patients.

Objectives To compare the capacity of ibrutinib (IB) and idelalisib-rituximab (IDELA-R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only. Methods A real-life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study. Results At an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA-R vs IB HR = 0.5, 95% CI = 0.36-0.71) although with some limitations due to the non-randomized and retrospective nature of the study and to the lower number of patients in the IDELA-R group (112 cases) related to the current prescribing practice. To overcome the potential problem of confounding by indication, we adjusted the association between the type of therapy and mortality for all variables significantly associated with OS at Cox univariate analysis. Furthermore, those variables, differently distributed between the two study groups, were introduced into the multivariate Cox model to improve the effectiveness of the analysis. By introducing all these variables into the multiple Cox regression model, we confirmed the protective effect of IB vs IDELA-R (HR = 0.67, 95% CI = 0.45-0.98, P = .04) independent of potential confounders. Conclusions Although our analysis presents some constraints, that is, the unavailability of additional potential confounders, and the retrospective nature of the study, this observation may be of help for the daily clinical practice, particularly in the absence of randomized trials comparing the two schedules.

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In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a “real-world” setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a “real-world” setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

Systemic Lupus Erythematosus (SLE), a well recognized systemic autoimmune disease is associated with an increased risk of malignancies, particularly lymphoma. Various studies have shown this risk to be as high as 4-7-fold compared to the general population. The pathogenesis of lymphoma in patients with SLE is still not well understood. In this review we summarize the world literature and update current knowledge on the interesting link between SLE and lymphomagenesis. We relate in turn to incidence rates of lymphoma in SLE and subtypes of lymphoma encountered; pathogenesis and relevant theories proposed; links with EBV and the possible role of continued activity of lupus and of immunosuppressive therapy in lymphomagenesis. It is clearly evident that further studies are needed to improve the understanding of this association. Some cytokines and proteins associated with cell survival and proliferation, such as BAFF, APRIL, IL6 and BCL2, have been found to be elevated both in SLE and lymphoma. These factors may well impact pathogenesis, however, a direct "cause and effect" relationship is yet to be demonstrated.

OBJECTIVE To evaluate disease characteristics and long-term outcomes in patients requiring second-line treatment following fludarabine, cyclophosphamide, and rituximab (FCR), for relapsed/refractory disease (R/R), or following discontinuation due to toxicities. METHOD A retrospective analysis of 126 chronic lymphocytic leukemia patients treated with frontline FCR: 63 received second-line treatment (41 relapsed, nine refractory [SD/PD], 13 prior toxicity). Time to next treatment (TTNT) was calculated from beginning FCR to initiation of second-line therapy. Overall and event-free survival was calculated from initiation of salvage treatment (OS2/EFS2). RESULTS Median follow-up for the entire cohort was 67 and 37 months from second-line therapy. TTNT

Patients with inflammatory bowel disease (IBD) on immunosuppression are at risk of developing lymphoma, particularly primary gastrointestinal (GI) tract non-Hodgkin lymphoma. Primary GI Hodgkin lymphoma (HL) in this setting, however, is rare and poorly defined. Here we review the available literature and also report a patient with Crohn's disease (CD) who developed GI HL. Our search yielded 12 single case studies and 7 case series involving 22 patients published between 1978-2016. Twenty-one (91%) patients had CD, and 2 had ulcerative colitis. The median age at lymphoma diagnosis was 39 years, and 18 (78%) patients were males. HL was diagnosed at a median of 8 years after IBD detection and 2 years after commencing immunosuppression. HL had a predilection (80%) to involve the inflamed GI site and the histological subtype was mixed cellularity in 65% of cases. In-situ hybridization for Epstein-Barr virus (EBV)-encoded RNA was positive in all documented cases. HL was diagnosed in stages I, II, IV in 35%, 20% and 45% of the patients, respectively. Notably, 66% of patients with advanced disease had liver involvement. Immunosuppression was stopped in most (69%) patients at HL diagnosis. Treatment used was either chemotherapy only, surgery followed by chemotherapy, or surgery alone in 50%, 33% and 16% of cases, respectively. Four patients had an IBD flare during HL remission. Patients with IBD who develop GI HL have distinct characteristics; male sex, predominance of CD, preference to develop in inflamed sites, mixed cellularity histology, EBV positivity, and a unique spread to the liver pattern.

Background/aim In chronic lymphocytic leukemia (CLL) the absolute neutrophil count (ANC) has generally been reported to be within normal limits and leukocytosis is due to absolute lymphocytosis. However, other cell types such as neutrophils and monocytes may also exceed the normal range in this disorder. The aim of this retrospective study was to evaluate the frequency and prognostic value of neutrophilia defined as an ANC>7×109/l and monocytosis- an absolute monocyte count (AMC)>1×109/l in 113 patients with chronic lymphocytic leukemia (CLL). Materials and methods We analyzed clinical and laboratory data from the records of patients with CLL followed in the Hematology unit of a tertiary hospital in Israel. Patients were categorized according to their ANC and AMC before treatment and their data compared. Results In 24 (21%) patients, neutrophilia was present at diagnosis while 40 (35%) had monocytosis. We identified that 9% of cases had neutrophilia with normal AMC. This subgroup of patients had a better prognosis with lower mortality rate, longer time-to-treatment interval and a higher rate of complete or partial response to treatment compared to patients without neutrophilia or monocytosis. Conclusion The presence of neutrophilia without monocytosis before treatment appears to be associated with a more favorable prognosis in CLL. These observations still need to be confirmed and validated in a larger cohort of patients.

Acquired amegakaryocytic thrombocytopenia (AAT), a rare entity characterized by severe thrombocytopenia and the absence of megakaryocytes in the bone marrow, may mimic or precede the diagnosis of aplastic anemia (AA). Here, we describe a patient who presented with apparent Epstein-Barr virus (EBV)-associated immune thrombocytopenia resistant to several lines of therapies, which was in fact a form of AAT with some features of AA. He eventually responded to therapy with eltrombopag, cyclosporine A (CSA), and antithymocyte globulin (ATG) and recovered completely. EBV infection is known to cause a variety of benign and malignant hematologic disorders, including bone marrow failure. However, to the best of our knowledge, this is the first case report of EBV-associated AAT. Treatment options for AAT are still not well defined, and even response to eltrombopag together with CSA and ATG does not always imply successful therapy. The natural history of EBV infection may well be sufficient to explain unexpected eventual recovery.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, characterized by the presence of long-lived circulating leukemic cells in the peripheral blood that may infiltrate all organs, particularly those of the reticulo-endothelial system. Liver enlargement and elevation of liver enzymes related to specific involvement by the underlying disease are well-recognized features in these patients. In CLL, the differential diagnosis of liver disorders is broad and includes liver infiltration by leukemic cells, immunologic manifestations associated with CLL, primary and secondary hepatic malignancies, drug-induced hepatotoxicity, infections, and Richter transformation. The above conditions can cause serious and even fatal complications such as acute liver failure. The aim of this study was to summarize all available published literature on hepatic manifestations encountered in CLL. This review contains sections on liver enlargement because of leukemic infiltration, autoimmune-induced hepatic dysfunction, acute liver failure, drug-induced liver toxicity, and associated malignancies. A high index of clinical suspicion and appropriate diagnostic evaluation, including liver biopsy in special circumstances, are important for both accurate diagnosis and deciding on the most appropriate treatment to prevent the development of fatal complications of acute liver failure.

Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis ( 1.8 vs not reached for ALC ≤ 0.7 at 9 months, P

In recent years, there have been major advances in the treatment of chronic lymphocytic leukemia (CLL) particularly since the development of novel therapeutic agents, mostly “biological drugs.” One of the obvious advantages of these agents is the decreased rate of infectious complications occurring during the course of therapy, compared to the use of standard immuno-chemotherapy regimens. Here, we describe 3 patients with CLL and 1 with mantle cell lymphoma who developed severe life-threatening pneumonias, during monotherapy with ibrutinib. The first case was a 70-year-old woman with relapsed CLL who developed bilateral pneumonia with hypoxia 1 week after starting ibrutinib. She did not respond to broad-spectrum antibiotics and was treated empirically with trimethoprim-sulphamethoxazole and improved. In the second case, we describe a 76-year-old woman with relapsed CLL who developed recurrent pneumonia after 3 years of treatment with ibrutinib. Presuming that ibrutinib was the cause of pneumonitis with secondary infection, it was stopped with subsequent improvement. The third patient a 67 year-old man died because of severe bilateral necrotizing pneumonia due to invasive aspergillosis and mucormycosis with pulmonary hemorrhage. The fourth patient with relapsed mantle cell lymphoma died because of severe bilateral pneumonia, caused by pseudomonas and candida, despite receiving appropriate antibiotics. From this experience, we hypothesize that the etiology of severe pneumonia associated with ibrutinib treatment is probably multifactorial, involving factors like preexisting immune-suppression, drug induced pneumonitis and infections. We suggest that patients with CLL or other lymphoproliferative disorders with suspected pneumonia during monotherapy with ibrutinib should be very carefully evaluated and need to undergo complete diagnostic workup to establish an exact diagnosis. Understanding which patients with CLL or lymphoma treated with kinase inhibitors are at a higher risk for developing pulmonary complications could be one of the important future challenges, when selecting the best available therapy for these patients.

In the HOVON68 CLL trial, patients 65 to 75 years of age had no survival benefit from the addition of low-dose alemtuzumab to fludarabine and cyclophosphamide (FC) in contrast to younger patients. The reasons are explored in this 5-year trial update using both survival analysis and competing risk analysis on non-CLL-related mortality. Elderly FCA patients died more frequently from causes not related to CLL, and more often related to comorbidity (mostly cardiovascular) than to infection. In a Cox multivariate analysis, del(17p), performance status >0, and comorbidity were associated with a higher non-CLL-related mortality in the elderly independent of the treatment modality. Thus, while the ‘fit’ elderly with no comorbidity or performance status of 0 might potentially benefit from chemo-immunotherapy with FC, caution is warranted, when considering alemtuzumab treatment in elderly patients with cardiovascular comorbidity.

A novel therapeutic approach in cancer, attempting to stimulate host anti-tumor immunity, involves blocking of immune checkpoints. Lymphocyte activation gene 3 (LAG3) is an immune checkpoint receptor expressed on activated/exhausted T cells. When engaged by the major histocompatibility complex (MHC) class II molecules, LAG3 negatively regulates T-cell function, thereby contributing to tumor escape. Intriguingly, a soluble LAG3 variant activates both immune and malignant MHC class II-presenting cells. In the study herein, we examined the role of LAG3 in the pathogenesis of chronic lymphocytic leukemia, an MHC class II-presenting malignancy, and show that chronic lymphocytic leukemia cells express and secrete LAG3. High levels of surface and soluble LAG3 were associated with the unmutated immunoglobulin variable heavy chain leukemic subtype and a shorter median time from diagnosis to first treatment. Utilizing a mechanism mediated through MHC class II engagement, recombinant soluble LAG3-Ig fusion protein, LAG3-Fc, activated chronic lymphocytic leukemia cells, induced anti-apoptotic pathways and protected the cells from spontaneous apoptosis, effects mediated by SYK, BTK and MAPK signaling. Moreover, LAG3 blocking antibody enhanced in vitro T-cell activation. Our data suggest that soluble LAG3 promotes leukemic cell activation and anti-apoptotic effects through its engagement with MHC class II. Furthermore, MHC class II-presenting chronic lymphocytic leukemia cells may affect LAG3-presenting T cells and impose immune exhaustion on their microenvironment; hence, blocking LAG3-MHC class II interactions is a potential therapeutic target in chronic lymphocytic leukemia.

A major revolution in the treatment of chronic lymphocytic leukemia (CLL) began with the approval of ibrutinib, a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK), for the treatment of relapsed/refractory (R/R) and/or TP53 mutated patients with CLL. However, 5 years later, some issues relating to this disorder still remain including the fact that with ibrutinib only a relatively small proportion of patients achieve complete remission and that ibrutinib-resistant CLL clones can develop in about 20% of patients. In addition, therapy must still be given continuously, and toxicities leading to drug discontinuation occur in about 30% of patients. In the meantime second-generation BTK inhibitors have already aroused considerable interest and gathered momentum. A possible strategy to overcome some of these obstacles is to combine ibrutinib with other targeted agents especially in high-risk disease, such as previously treated refractory patients or those with TP53 aberrations or complex karyotypes, in whom rapid eradication of disease is most desirable. Therapy with single agent ibrutinib should be part of a sequential approach for patients with low risk disease, especially in older patients (aged >70 years) with a higher burden of comorbidities. Long-term results of ongoing studies combining Ibrutinib with (chemo)-immunotherapy or other targeted agents are eagerly awaited. Future clinical trials are indeed still needed to provide answers to these open questions.

The annual meeting of the International Splenic Lymphoma Study Group (ISLSG) was held at the Josep Carreras Leukemia Research Institute (Badalona, Barcelona, Spain) on the 17th and 18th of May 2019...

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

In the past decade the introduction of targeted therapies has dramatically transformed the landscape of treatment for chronic lymphocytic leukemia (CLL). Whether this new therapeutic scenario will modify the current prevalence statistics and natural history of autoimmune cytopenias complicating CLL is still a matter of debate. Here we present a comprehensive review of the literature on this topic, with special emphasis on the incidence of autoimmune hemolytic anemia (AIHA). The potential to induce autoimmune cytopenia has been studied mostly with ibrutinib, a first- in-class bruton kinase (BTK) inhibitor, licensed for the treatment of relapsed/refractory high-risk CLL. Recent observations suggest that emergent AIHA occurring during therapy with ibrutinib is more an expression of CLL activity than an ibrutinib-mediated process. Since available information on AIHA occurring during and after therapy with small-molecule kinase inhibitors relies mainly on data collected from clinical trials, a close post- marketing surveillance is mandatory in order to improve our understanding of this topic.

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.

I In the last decade, the B-cell receptor has emerged as a pivotal stimulus in the pathogenesis of chronic lymphocytic leukemia, and a very feasible therapeutic target in this disease. B-cell receptor responsiveness in chronic lymphocytic leukemia cells is heterogeneous among patients and correlates with aggressiveness of the disease. Here we show, for the first time, that SLP76, a key scaffold protein in T-cell receptor signaling, is ectopically expressed in chronic lymphocytic leukemia cells, with variable levels among patients, and correlates positively with unmutated immunoglobulin heavy chain variable gene status and ZAP-70 expression. We found that SLP76 was functionally active in chronic lymphocytic leukemia cells. A SYK-dependent basal level of phosphorylated SLP76 exists in the cells, and upon B-cell receptor engagement, SLP76 tyrosine phosphorylation is significantly enhanced concomitantly with increased physical association with BTK. B-cell receptor-induced SLP76 phosphorylation is mediated by upstream signaling events involving LCK and SYK. Knockdown of SLP76 in the cells resulted in decreased induction of BTK, PLCγ2 and IκB phosphorylation, as well as cell viability after B-cell receptor activation with anti-IgM. Consistent with our biochemical findings, high total SLP76 expression in chronic lymphocytic leukemia cells correlated with a more aggressive disease course. In conclusion: SLP76 is ectopically expressed in chronic lymphocytic leukemia cells where it plays a role in B-cell receptor signaling.

Previous studies have shown an increase risk of second malignancies after non-Hodgkin's lymphoma (NHL), which is probably related to a combination of factors including genetic predisposition, molecular background, host immunological status and therapy administered. Here, we determined the incidence of NHL and risk of second solid tumours and haematological malignancies among survivors of NHL diagnosed in Israel during 1980-2011. Data were collected from the records of the Israeli National Cancer Registry. The total cohort of 24 666 NHL-patients included 22 601 Jews and 2065 Arabs. Median age of diagnosis for Jews was 61.3 years and 48.2 for Arab patients. Of the Jews with NHL, 11 265 (50%) were of European-American origin, 5005 (22%) Asian or African and 6114 (27%) were born in Israel. Second cancers were recorded in 2010 NHL survivors, 1918 Jews and 92 Arabs, representing a rate of 8.5%, and 4.5% o, respectively. Second malignancies in all recorded sites were more frequent than in the general population, with a standardized incidence ratio (SIR) of 1.28 for Jewish men, 1.25 for Jewish women, 1.73 for Arab men and 1.98 for Arab women. This higher risk was even more pronounced for the 309 cases with secondary haematological malignancies (secondary haematological malignancies of 1.97, 1.81, 4.48 and 4.15, respectively). Our findings show that there is an increased risk of second malignancies occurring after diagnosis of NHL in Israel, particularly for haematological malignancies such as leukaemia and NHL. The differences we report in the incidence of NHL and the types of second malignancies occurring among Jews and Arabs suggest that ethnicity and genetic susceptibility may be important relevant risk factors. Copyright © 2016 John Wiley & Sons, Ltd.

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.

Patients with rheumatoid arthritis (RA) have a greater risk of developing both Hodgkin lymphoma (HL) and non-HL than the general population. Non-Hodgkin lymphoma is more common than HL in these patients, and diffuse large B cell lymphoma is the most frequent subtype observed. Although the clinical course of lymphoma in RA is often aggressive, the prognosis in these cases is similar to that of lymphoma in the general population. In this review, we summarize data derived from both retrospective and prospective studies, regarding incidence, pathogenesis, and outcome of lymphomas in RA patients and outline the possible mechanisms and hypotheses linking these 2 disorders. Over the years, 3 main theories have been suggested to explain this association. These hypotheses relate to genetic predisposition, persistence of long standing disease activity with continued immune stimulation, and the role of anti-RA therapy given. A common genetic predisposition linking RA and lymphoma has not been established. As for treatment of RA, this includes immunosuppressive antitumor necrosis factor drugs or conventional disease modifying antirheumatic drugs like methotrexate. Neither of these drug categories appears to be associated with a higher risk of lymphoma in RA. The impact of continuing disease activity and immune stimulation appears to be the most significant in lymphomagenesis in these patients.

Patients with chronic lymphocytic leukemia (CLL) have more than twice the risk of developing second neoplasms than the normal population [1]. A retrospective study from the MDACC in Houston on 2028...

Bendamustine is being increasingly used in patients with indolent non-Hodgkin lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia. This review summarizes available evidence regarding the effects of bendamustine on the immune system, examines its role in consequent infections as reported in randomized controlled trials, prospective observational investigations, retrospective studies and individual published case reports. Myelosuppression including lymphopenia occurs relatively frequently after therapy with bendamustine. It is mostly CD4 + T cell counts that are suppressed, yet when given in combination with rituximab, both T cell and B cell depletion have been recorded. In addition, hypogammaglobulinemia after bendamustine therapy has also been reported. Variable infection rates have been documented and these include different bacterial, viral and fungal infections. Finally, we also consider issues relating to the use of prophylactic antibiotics in patients receiving the drug.

The risk of developing non-Hodgkin lymphoma increases with age, yet elderly patients are under-represented in clinical trials. Here, we evaluate a combination regimen including ifosfamide, carboplatin and etoposide with or without rituximab (ICE ± R) in 32 fit elderly patients (median age 75.6 years) with relapsed or refractory diffuse large B-cell lymphoma. ICE ± R was generally administered in reduced doses and was well tolerated. The overall response rate (ORR) was 53.1% with a complete response (CR) rate of 40.6%. The median progression free survival (PFS) and overall survival (OS) were 3.9 and 17.0 months, respectively. Patients who responded to ICE ± R achieved median PFS of 47.2 months and OS of 78.9 months. Patients ineligible for autologous transplantation who responded to ICE ± R were treated with additional cycles, and achieved a median PFS of 18.9 months and OS of 21.7 months. Previous response to first-line therapy was the strongest predictor of response, PFS and OS to second-line treatment.

Over the last 20 years there have been sustained and dramatic improvements in the therapy of chronic lymphocytic leukemia (CLL). Until 1990, therapy for CLL was based on alkylating agents, chlorambucil and cyclophosphamide, which did not impact meaningfully on overall survival. The more recent therapeutic regimens, built on combination chemoimmunotherapy, achieve complete responses in 40-50% of cases. However, these regimens are limited in their applicability mostly to the treatment of younger and physically fit patients due to their associated toxicity. Furthermore, since disease progression and drug resistance are considered inevitable, CLL remains incurable. Fortunately, significant progress in the understanding of CLL biology has enabled the development of new molecular drugs targeting the B-cell receptor signaling pathway, such as ibrutinib and idelalisib, which have shown impressive results in patients with relapsed/refractory disease or with TP53 mutation/deletion. Furthermore, obinutuzumab, a type II anti-CD20 antibody, which results in direct cell death and antibody-dependent cell-mediated cytotoxicity, also has proven efficacy when used in combination with chlorambucil in previously untreated and unfit patients. All these three new drugs have recently received FDA approval for the treatment of CLL. This review focuses on the role of ibrutinib, idelalisib and obinutuzumab in therapy of CLL.