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Simple Summary: Double/triple-hit lymphomas (DHLs/THLs) are an aggressive type of high-grade B-cell lymphomas (HGBLs), characterized by translocations in MYC and BCL2/BCL6. DHL patients respond poorly to standard chemoimmunotherapy regimens; thus, timely and accurate diagnosis is of paramount importance for their proper clinical management. The standard technique used for the identification of these translocations is fluorescence in situ hybridization (FISH), which is not routinely performed at every medical center to all potential patients. In the current study, we employed an image-based, artificial intelligence, deep learning algorithmic tool for the identification of DHL/THL cases by analyzing scanned histopathological H&E-stained tissue slide images. Our preliminary results demonstrate high performances, suggesting the potential use of such a solution in the clinical workflow to support the management of HGBL patients. Deep learning applications are emerging as promising new tools that can support the diagnosis and classification of different cancer types. While such solutions hold great potential for hematological malignancies, there have been limited studies describing the use of such applications in this field. The rapid diagnosis of double/triple-hit lymphomas (DHLs/THLs) involving MYC, BCL2 and/or BCL6 rearrangements is obligatory for optimal patient care. Here, we present a novel deep learning tool for diagnosing DHLs/THLs directly from scanned images of biopsy slides. A total of 57 biopsies, including 32 in a training set (including five DH lymphoma cases) and 25 in a validation set (including 10 DH/TH cases), were included. The DHL-classifier demonstrated a sensitivity of 100%, a specificity of 87% and an AUC of 0.95, with only two false positive cases, compared to FISH. The DHL-classifier showed a 92% predictive value as a screening tool for performing conventional FISH analysis, over-performing currently used criteria. The work presented here provides the proof of concept for the potential use of an AI tool for the identification of DH/TH events. However, more extensive follow-up studies are required to assess the robustness of this tool and achieve high performances in a diverse population. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cells (CAR‐T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR‐T cell therapy in patients with extra‐nodal (EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR‐T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)‐only and 12 of 126 (10%) showed no disease assessed by PET‐CT. There were no significant differences in CAR‐T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 [95% CI: 7.8–13.6] vs. 14.1 [95% CI: 10–18.1] months, p =.126). Similarly, median overall survival (OS) was not significantly different (15.36 [95% CI 12.5–18.2] vs. 18.4 [95% CI 14.8–22.1] months, p =.100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months [95% CI 9–15.5] vs. 4.28 months [95% CI 0.6–7.9], p =.010) compared to patients with >2 EN sites, respectively (16.5 months [95% CI 13.4–19.6] vs. 8.7 months [95% CI 4.6–12.8], p =.05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p =.021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis. [ABSTRACT FROM AUTHOR]

Anti CD-19 chimeric antigen receptor T (CAR-T) cells demonstrate effective early anti-tumor response; however, impaired hematopoietic recovery is observed in about 30% of patients with prolonged cytopenia appearing as an unmet need for optimal treatment. All adult patients given commercially available anti CD-19 CAR-T for diffuse large B cell lymphoma (DLBCL) were screened at 21–28 days after CAR-T infusion for cytopenia. In case of severe persistent cytopenia, patients were given TPO receptor agonists. Initial dose of eltrombopag was 50 mg/day and gradually increased to a maximal dose of 150 mg/day. Romiplostim was given as subcutaneous injection once a week for 2 doses (125 mcg). Response was defined as transfusion independency along with resolution of severe neutropenia (ANC > 500 /microL) and/or platelets > 20,000/microL for three consecutive values on different days. TPO receptor agonists were tapered down when response was met. From May 2019 to December 2021, 93 patients were eligible (74%, tisagenlecleucel and 26%, axicabtagene ciloleucel). The median age was 69 (range, 19–85) years. Six patients (6.5%) (tisagenlecleucel, n = 4 or axicabtagene ciloleucel, n = 2) demonstrated prolonged severe cytopenia and were treated with TPO receptor agonists (eltrombopag, n = 4; romiplastim, n = 1, both drugs, n = 1). Median time from CAR-T infusion to initiation of TPO receptor agonist was 43 (range, 21–55) days. All patients were transfusion-dependent and were given daily GCSF prior to TPO receptor agonist administration. Response to TPO receptor agonists was seen in all 6 patients. Median time from TPO receptor agonist initiation to resolution of cytopenia was 22 (range, 8–124) days for Hb, 27 (range, 6–38) days for platelets, and 29 (range, 7–61) days for neutrophils. A complete resolution of all blood counts (ANC > 500 /microL and platelets > 20,000/microL and hemoglobin > 8 gr/dL) was seen in 5/6 patients. No toxicity was observed during the therapy course. This paper supports further investigation of TPO receptor agonists in the treatment of persistent cytopenia following CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Polatuzumab (Pola)-based regimens and chimeric antigen receptor T (CAR T) cells provide superior outcome compared to conventional chemoimmunotherapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Choosing between these strategies remains controversial. The efficacy of CAR T versus Pola-rituximab(R) /Pola-bendamustine(B)-R in R/R DLBCL patients after failing ≥2 lines of treatment was compared in a retrospective, 'real-world' study. Propensity score matching, for age, lymphoma category (de-novo/transformed), number of prior lines, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level, was applied to control for differences in patients' characteristics. Response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 82 patients, treated with CAR T (n=41) or Pola-based regimens (n=41), were included. No treatment-related deaths occurred with CAR T vs. 3 (7.3%) with Pola. The overall and complete response rates were 83% and 58% with CAR T vs. 66% and 44% with Pola-based-regimens (p=0.077 and p=0.18, respectively). At a median follow-up of 9 months (range 1-19.2) and 16 months (range 0.7-25.3) for the CAR T and Pola arm respectively, the median PFS has not been reached for CAR T vs. 5.6 months for Pola (95% CI 3.6-7.6, p=0.014). Median OS has not been reached for CAR T vs. 10.8 months (95% CI 2.2-19.4) for Pola (p=0.026). To conclude, in a real-world setting, treatment with CAR T achieved superior PFS and OS compared to Pola-based regimens in patients with R/R DLBCL. [ABSTRACT FROM AUTHOR]

Most infected patients are unaware of their past exposure to HBV, which may have resolved B ( b past HBV infection, diagnosed by HB surface antigen (HBsAg)-negative and HB core antibody (HBcAb)-positive serology] or that they have chronic HBV infection [(CHB) HBsAg - positive)]. It is estimated that more than two billion people worldwide have been exposed to hepatitis B virus (HBV), with more than 260 million people actively infected with HBV, making HBV one of the leading causes of chronic liver disease, cirrhosis and hepatocellular carcinoma [[1]]. In addition, Dominguez et al., reported a patient with CLL with past HBV infection, who had HBVr almost 5 years after completion of FCR. An alternative pathway is monitoring HBsAg and HBV DNA every 3 months, during anticancer therapy and for up to 12 months after last anticancer therapy, with immediate preemptive antiviral therapy (during anticancer therapy and for up to 12 months after last anticancer therapy), if HBV reactivation is detected [[11]]. [Extracted from the article]

It is unknown whether rituximab increases the risk of second primary malignancies (SPMs) in patients with diffuse large cell B-cell lymphoma (DLBCL). We assessed SPMs in DLBCL patients diagnosed between 1996 and 2014 in comparison with the general Israeli population and dependent on rituximab treatment. Jewish patients had no increased risk for SPMs. Arab-DLBCL females had a higher SPMs rate compared to the general Arab-females population [SIR (95%CI) 1.86 (1.08–2.98)]. Incidence and time to SPMs, in both Jewish and Arab patients, were unaffected by rituximab. Risk for breast and thyroid cancers, in Arab and Jewish females respectively, were higher in the pre-rituximab era [SIR(95%CI) 5.25 (1.41–13.43) and SIR(95%CI) 3.85 (1.41–8.38), respectively]. Age ≥60 years was the only predictor for increased risk of SPM (HR = 2.5, p <.01). The increased risk of SPMs in specific subgroups of patients that were treated in the pre-rituximab era may reflect stringent medical surveillance employed in these populations. [ABSTRACT FROM AUTHOR]

High-dose therapy followed by autologous hematopoietic cell transplantation (HCT) prolongs overall survival in patients under 65 years old with relapsed aggressive lymphoma. We aimed to explore the toxicity and efficacy of HCT in patients over 65 years with aggressive lymphoma compared with younger patients. We compared the transplantation outcomes between patients ≥ 65 years (n = 58) and 55-64 years (n = 44) with chemosensitive aggressive lymphoma (DLBCL, MCL and TCL) that underwent HCT between 1999 and 2016 in the Tel-Aviv Medical Center. The median age was 68 (range, 65-74) and 61 (range, 55-64) years, respectively. There were no differences in the incidences of grade 3-4 mucositis, documented infections and pulmonary complications between the two groups. There was no difference in the incidences of secondary malignancies, relapse (p = .26), non-relapse mortality, (p = .77) and overall survival (p = .53). Multivariate analysis revealed that smoking was a risk factor for non-relapse mortality, while partial remission and > 2 lines of treatment prior HCT were associated with higher risk for relapse. Psycho-socioeconomic score was associated with prolonged hospitalization after HCT and recurrent hospitalizations. We conclude that patients ≥ 65 years old with aggressive lymphoma, compared to younger counterparts, have similar transplantation outcome. Improving habits and psychosocial factors may further improve outcomes in these patients. [ABSTRACT FROM AUTHOR]

Endurance, marathon-type exertion is known to induce adverse changes in the immune system. Increased airway hyper-responsiveness and airway inflammation are well documented in endurance athletes and endurance exercise is considered a major risk factor for asthma in elite athletes. Yet, the mechanisms underlying this phenomenon are still to be deduced. We studied the effect of strenuous endurance exercise (marathon and half-ironman triathlon) on CD4+ lymphocyte sub-populations and on the balance between effector and regulatory CD4+ lymphocytes in the peripheral blood of trained athletes, Endurance exercise induced a significant increase in Th17 cells and a sustained decrease in peripheral blood regulatory T cells (Tregs). While interleukin (IL)-2 levels remained undetectable, post-race serum IL-6 and transforming growth factor (TGF) β levels were significantly elevated. Treg levels in sedentary controls' decreased in vitro after incubation with athletes' post-exercise serum, an effect that was attenuated by supplements of IL-2 or anti IL-6 neutralizing antibodies. Our data suggest that exercise-induced changes in serum cytokine levels promote alterations in Tregs and Th17 cell populations, which may divert the subtle balance in the immune system towards inflammation. This may explain allergic and autoimmune phenomena previously reported in endurance athletes and contribute to our understanding of exercise-related asthma. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding a study on the correlation between Th17 cell counts and Tregs peripheral blood lymphocytes in patients with early stage chronic lymphocytic leukemia (CLL).

Chronic lymphocytic leukemia (CLL) cells depend on their microenvironment for proliferation and survival. Ectonucleotidase CD39 has anti-inflammatory properties as it hydrolyzes proinflammatory extracellular ATP, generates anti-inflammatory adenosine, and also protects regulatory T cells from ATP-induced cell death. In this study, we investigated the clinical significance of CD39 expression on CD4 T cells in 62 patients with CLL as well as its compartmental regulation and explored the possible mechanisms for its induction. Compared to healthy individuals, CD4CD39 lymphocytes were increased in the peripheral blood of patients with CLL and correlated with the advanced stage of disease. CD4CD39 cells were also higher in patients with CLL, who needed therapeutic intervention, and in those who had unmutated immunoglobulin heavy chain variable region gene, were ZAP70 or had β2-microglobulin levels of >3 g/L. There were more CD4CD39 lymphocytes in the bone marrow compartment than in the peripheral blood, and in vitro studies showed that CD39 can be induced on CD4 cells by exposure to ATP or indirectly, following B cell receptor engagement. This may support the notion that the leukemic cells contribute to create an immune-subversive environment, and perhaps to a poorer prognosis. CD39 may also serve as a future target for the development of novel therapies with immune-modulating antitumor agents in CLL. [ABSTRACT FROM AUTHOR]

Background: 18Fluoro-2-deoxyglucose (18FDG) positron emission tomography (PET) is widely used for initial staging and follow-up in patients with malignant lymphoma. While earlier studies suggested a limited role for PET in extranodal marginal zone mucosa-associated lymphoid tissue (MALT) lymphoma patients due to their non-FDG avidity, more recent reports have suggested that the issue is controversial. In the present study, we evaluated the diagnostic accuracy of PET integrated with CT (PETCT) in patients with MALT lymphoma and assessed its reliability in clinical staging and monitoring response. Methods: Thirty-three patients with biopsy proven MALT lymphoma in 37 sites, who underwent PET/CT at diagnosis, were enrolled. Medical records, PET/CT findings and data obtained by other diagnostic procedures were reviewed. Results: Common sites of MALT lymphoma were the stomach (18), lung (5), orbit (4), and parotid gland (3). PET/CT detected active disease in 18 of 33 patients (54.5%) at diagnosis. Sensitivity in gastric MALT (38.9%) was lower when compared with non-gastric MALT (75%). PET/CT detected active disease in 100% patients with advanced disease (stage III–IV) but only in 42.3% with early stage disease (I–II). The incidence of gastric FDG uptake was higher in patients showing gastric ulcer on gastroscopy than in subjects with minimal or no macroscopic findings. Of the 33 patients in the study cohort, 12 had a follow-up PET/CT which detected relapse in three patients. Conclusions: These data suggest that PET/CT is a useful tool for both, initial staging and follow-up after therapy in patients with MALT lymphoma. Its sensitivity depends on disease location and stage at initial diagnosis. [ABSTRACT FROM AUTHOR]

Background: In the light of an emerging role for early-mid treatment 18 F-deoxyfluoroglucose positron emission tomography (FDG-PET) as an important prognostic indicator in aggressive non-Hodgkin’s lymphoma (NHL) , we attempted to determine whether a simple parameter, such as the early-mid treatment CRP (C-reactive protein) level, could also be utilized as a significant prognostic factor in aggressive NHL. Patients and methods: Serum CRP levels were monitored in 55 patients with aggressive NHL. The lowest value of the early mid-term CRP levels recorded was compared with the interim PET-CT results, as well as with the clinical course and eventual outcome. Results: During chemotherapy, the lowest value of early-mid treatment CRP levels significantly predicted the results of the interim FDG-PET ( P = 0.04 with an odds ratio of 1.13). Patients who did not achieve an early-mid treatment CRP level of <5 mg/L, had a shorter time to disease progression or relapse ( P = 0.001) as well as a reduced overall survival (OS) ( P = 0.016). Conclusions: The early-mid treatment serum CRP level is a prognostic factor in aggressive NHL. Patients who do not achieve an early-mid treatment level of <5 mg/L have quicker disease progression or earlier relapse and also appear to have an inferior OS. [ABSTRACT FROM AUTHOR]

The cyclic adenosine monophosphate (AMP) response element-binding protein, CREB, often modulates stress responses. Here, we report that CREB suppresses the glioblastoma proliferative effect of the stress-induced acetylcholinesterase variant, AChE-R. In human U87MG glioblastoma cells, AChE-R formed a triple complex with protein kinase C (PKC) ε and the scaffold protein RACK1, enhanced PKCε phosphorylation, and facilitated BrdU incorporation. Either over-expressed CREB, or antisense destruction of AChE-R mRNA, PKC, or protein kinase A (PKA) inhibitors--but not CREB combined with PKC inhibition suppressed-this proliferation, suggesting that CREB's repression of this process involves a PKC-mediated pathway, whereas impaired CREB regulation allows AChE-R-induced, PKA-mediated proliferation of glioblastoma tumors. [ABSTRACT FROM AUTHOR]

To study the regulation of acetylcholinesterase (AChE) gene expression in human brain tumors, 3′ splice variants of AChE mRNA and potentially relevant transcription factor mRNAs were labeled in primary astrocytomas and melanomas. AChE-S and AChE-R mRNA, as well as Runx1/AML1 mRNA accumulated in astrocytomas in correlation with tumor aggressiveness, but neither HNF3β nor c-fos mRNA was observed in melanoma and astrocytomas. Immunohistochemistry demonstrated nuclear Runx1/AML1 and cellular AChE-S and AChE-R in melanomas, however, only AChE-S, and not the secreted AChE-R variant, was retained in astrocyte tumor cells. Runx1/AML1 revealed weak linkage with ACHE promoter sequences, yet enhanced ACHE gene expression in co-transfected COS1 cells. The p300 co-activator and the ACHE promoter's distal enhancer facilitated this effect, which was independent of much of the Runx1/AML1 trans-activation domain. Surprisingly, GASP, a fusion product of green fluorescence protein (GFP) and ASP67, a peptide composed of the 67 C-terminal amino acid residues of AChE-S, localized to COS1 cell nuclei. However, GARP, the corresponding fusion product of GFP with a peptide having the 51 C-terminal residues of AChE-E or GFP alone, remained cytoplasmic. Runx1/AML1 exhibited improved nuclear retention in GASP-expressing COS1 cells, suggesting modulated nuclear localization processes. Together, these findings reveal brain tumor-specific regulation of both expression and cellular retention of variant ACHE gene products.Oncogene (2002) 21, 8428–8441. doi:10.1038/sj.onc.1205945 [ABSTRACT FROM AUTHOR]

Haematopoiesis, the differentiation of haematopoietic stem cells and progenitors into various lineages, involves complex interactions of transcription factors that modulate the expression of downstream genes and mediate proliferation and differentiation signals. Commitment of pluripotent haematopoietic stem cells to the erythroid lineage induces erythropoiesis, the production of red blood cells. This process involves a concerted progression through an erythroid burst forming unit (BFU-E), an erythroid colony forming unit (CFU-E), proerythroblast and an erythroblast. The terminally differentiated erythrocytes, in mammals, lose their nucleus yet function several more months. A well-coordinated cohort of transcription factors regulates the formation, survival, proliferation and differentiation of multipotent progenitor into the erythroid lineage. Here, we discuss broad-spectrum factors essential for self-renewal and/or differentiation of multipotent cells as well as specific factors required for proper erythroid development. These factors may operate solely or as part of transcriptional complexes, and exert activation or repression. Sequence comparisons reveal evolutionarily conserved modular composition for these factors; X-ray crystallography demonstrates that they include multidomain elements (e.g. HLH or zinc finger motifs), consistent with their complex interactions with other proteins. Finally, transfections and genomic studies show that the timing of each factor's expression during the hematopoietic process, the cell lineages affected and the existing combination of other factors determine the erythroid cell fate. [ABSTRACT FROM AUTHOR]

Runx1/AML1, a chromosome 21q22 hematopoietic regulator, is frequently translocated in leukemia. Its protein product, a relatively weak transcriptional activator, becomes an effective transcriptional enhancer or repressor, when co-operating with transcriptional co-activators or co-repressors. Runx1/AML1 association with its partners is disrupted in leukemia. For example, Runx1/AML1 mutations and translocations (e.g. t(8;21), t(12;21) and t(3;21)) impair binding of Runx1/AML1–CBFβ complexes to Runt motifs in myelopoietically active promoters, preventing normal hematopoiesis. However, Runx1/AML1-associated translocations are not leukemogenic in animal models, suggesting the involvement of yet unidentified regulatory proteins. New candidates are cholinesterases, inhibition of which increases leukemic risk in a manner potentially associated with Runx1/AML1. [Copyright &y& Elsevier]

In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience with a five-day course of dual anti-viral treatment with remdesivir and nirmatrelvir/ritonavir for hemato-oncological immunocompromised patients with persistent COVID-19. Fifteen patients with a history of lymphoma, CLL, and MM were included. Eight were male, median age was 74. All patients had an immediate clinical and virological response. In 73 % of patients, PCR for SARS-CoV-2 became negative at the end of treatment and the rest had an increase in PCR cycle threshold (CT) values, with a median increase of 6 cycles. After a follow-up of three months, 60 % of patients remained in full clinical and virological remission. None required invasive mechanical ventilation or died. The side effects we observed, neutropenia, lactatemia and elevated transaminases, were mild and almost all transient in nature. We conclude that dual anti-viral treatment appears to be a valid treatment option for persistent COVID-19. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric Antigen Receptor T-cell (CAR T) therapy has become the preferable therapeutic approach in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Detection of CAR Ts in peripheral blood smear (PBS) is challenging due to the low sensitivity of current morphological technologies. We provide herein a morphological analysis of CAR Ts during the production process and in consecutive PBS obtained from DLBCL patients undergoing CAR T therapy, employing a novel, highly sensitive microscopy platform. We found that activated morphology was attributed predominantly to transduced cells following engagement with target cells. The average number of day 5 CAR Ts, and their sustained presence, were significantly higher in patients obtaining complete response. Also, a high number of CAR Ts was associated with longer cytokine storm release syndrome. These data indicate that CAR T morphological surveillance in PB might serve as a simple, fast and inexpensive method to provide clinically relevant insights. Chimeric Antigen Receptor T-cell (CAR T) therapy has become the preferable treatment in relapsed/refractory diffuse large B-cell lymphomas (DLBCL) patients. Detection of CAR Ts in peripheral blood smear (PBS) is challenging due to insufficient data regarding their morphology and low sensitivity. The morphological evolution of CAR Ts along their production process, and in patients, was established by Full-Field Morphology (FFM), a novel digital microscopy approach that provides highly sensitive PBS analysis. At day 8 of production, 42.7 ± 10.8% of the CAR T transduced cells exhibited activated morphology compared with 9.3 ± 3.8% in untransduced cells. Moreover, engagement of transduced CAR Ts with target cells resulted in further morphological transformation into activated morphology (83 ± 5.6% of the cells). In patients, the average number of day 5 CAR Ts, and their sustained presence, were significantly higher in patients obtaining complete response. A high number of activated morphology CAR Ts at day 14 was associated with prolonged cytokine release storm. Overall, CAR Ts exhibited heterogeneous morphology, with the activated morphology attributed predominantly to transduced cells following engagement with target cells. Post-transfusion CAR T detection was associated with increased complete responses. FFM CAR T surveillance in PBS may serve as a simple inexpensive method to provide clinically relevant insights into this treatment modality. [ABSTRACT FROM AUTHOR]

In this article the authors discuss lenalidomide and T-cell homeostasis and the article "Lenalidomide Consolidation and Maintenance Therapy After Autologous Stem Cell Transplant for Multiple Myeloma Induces Persistent Changes in T-cell Homeostasis" by E. Clave, C. Douay, T. Coman et al. within the issue. They are cautiously supportive of several points raised in Clave et al.'s article and suggest that the article leads to more questions about the use of lenalidomide for treating cancers.

The author comments on a research study which examined the link of regulatory T-cells (Tregs) to the prognosis of chronic lymphocytic leukemia (CLL). A discussion on the relation between peripheral blood Tregs and the severity of CLL at diagnosis, during disease progression and at the time of development of autoimmune cytopenia in Indian patients is presented. The author agrees with the inverse correlation between the percentage and absolute Treg cell numbers and lymphocyte doubling time (LDT).

In this article the author discusses the expansion mechanism of regulatory T-cells (Tregs) in B chronic lymphocytic leukemia (CLL). It states that Tregs have an ability to inhibit anti-tumor immune responses. It cites the study by Jak and colleagues which rejected the notion that chronic antigenic stimulation induces Treg expansion in CLL due to reduced apoptosis. It concludes that Treg expansion results from T and B cell activation that lead to CLL cell immune avoidance.

Objectives: To evaluate the role of additional chemotherapy before autologous hematopoietic cell transplantation (HCT) in patients with relapse/refractory diffuse large B‐cell lymphoma (DLBCL) who achieve partial remission following first salvage therapy. Methods: We conducted a multicenter retrospective study of all adult patients with DLBCL who underwent HCT between 2008 and 2020 and achieved partial response (PR) after the first salvage and were either referred directly to HCT (n = 47) or received additional salvage therapy before HCT (n = 22). Results: Post‐HCT CR rate and progression‐free survival were comparable between the two groups (66% vs. 68%, p =.86 and median not reached vs. 10.2 months [95% confidence interval, CI 7.1–12.3], p =.27, respectively). Median overall survival (OS) and estimated 3‐year OS favored patients who were directly referred to HCT (105.8 [95% CI 63–148] months vs. 14.5 [95% CI 0–44] months, p =.035, and 65% [95% CI 51%–75%] vs. 40% [95% CI 21%–53%], p =.035, respectively). In Cox regression model, while International Prognostic Index and primary refractory versus relapse disease did not impact OS, allocation to a second salvage regimen and older age were both associated with inferior survival (hazard ratio [HR] = 2.57 95% CI 1.1–5.8, p =.023 and HR = 1.04 95% CI 0.99–1.2, p =.064, respectively). Conclusions: Referring patients with chemotherapy‐sensitive disease in PR directly to HCT is associated with better OS compared to those receiving additional lines of treatment. [ABSTRACT FROM AUTHOR]

Objective: To determine the rate of lymphoproliferative disease (LPD) in women undergoing routine breast cancer screening (BCS). BCS can reveal pathologies other than carcinoma that involve the breast and lymph tissue. The few studies that have described cases in which BCS led to the diagnosis of LPD were based on small series and focused on imaging rather than clinical characteristics. Setting and Methods: A multi-center retrospective study in Israel, investigating LPD rate and characteristics among women diagnosed with LPD via BCS. Results: Thirty-four patients out of 14,400 consecutive women undergoing BCS at Tel Aviv Sourasky Medical Center during the study period were diagnosed with LPD, suggesting a diagnosis rate of 0.24%. The enlarged cohort (n = 45), including 11 patients that were retrieved from the databases of three other centers, demonstrates a predominant histological diagnosis of non-aggressive LPD (n = 33). Thirty-four (76%) had a suspicious axillary lymph node, and 11 had a breast lesion. The median maximal lesion size was 1.95 cm (range 0.8–6.5). Disease was localized in 60% of patients (stage 1 and 1E). Univariate analysis revealed that lymphocyte count was inversely associated with aggressive histology. At median follow-up of 39 months, all but three patients were alive. These three had been diagnosed with non-aggressive LPD which had never been treated and died from unrelated causes. Conclusions: The LPD detection rate via BCS was 2.36 per 1000 screens. The majority of LPDs were non-aggressive. Nearly a third were aggressive, most detected at an early stage, and the clinical outcome was generally favorable. [ABSTRACT FROM AUTHOR]

BACKGROUND Primary splenic diffuse large B-cell lymphoma (PS-DLBCL), an uncommon type of non-Hodgkin lymphoma, has been investigated only in small patient series before the rituximab era. The therapeutic role of splenectomy in addition to immunochemotherapy is unknown. METHODS The databases of 7 medical centers in Israel were searched for patients diagnosed with PS-DLBCL in 1982-2013, and clinical, treatment, and outcome data were collected for 87 patients. The mean patient age was 59.6 years; 57.5% were male. RESULTS Patients presented with abdominal pain (81%), B symptoms (59%), splenomegaly (84%), splenic masses (97%), and high lactate dehydrogenase (LDH) levels (84%); 61% had stage I or II disease. The diagnosis was made with core-needle biopsy in 46 patients and with diagnostic splenectomy in 39 patients. Eighty patients (92%) were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone; 68 (78%) received rituximab. A complete response was achieved in 67 patients (77%), and a partial response was achieved in 8 (9%). At 5 years, the overall survival (OS) rate was 77%, and the progression-free survival (PFS) rate was 67%. When patients were stratified by splenectomy at diagnosis, the OS rates were 91% for splenectomized patients and 68% for nonsplenectomized patients ( P = .08), and the PFS rates were 85% and 55%, respectively ( P = .02). The respective values for the subgroup with early-stage disease were 96% and 63% for OS ( P = .009) and 90% and 51% for PFS ( P = .01). In a multivariate analysis, a low Eastern Cooperative Oncology Group performance status and splenectomy independently predicted better PFS ( P < .03). CONCLUSIONS Patients with PS-DLBCL usually present with abdominal pain, high LDH levels, and a splenic mass. This study shows for the first time that splenectomy at diagnosis improves survival, specifically in patients with early-stage disease. Cancer 2015;121:2909-2916. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Summary: This prospective study evaluated seroconversion rates in response to BNT162b2 (Pfizer‐BioNTech) COVID‐19 vaccine booster in 44 B‐cell non‐Hodgkin lymphoma (B‐NHL) patients who failed to respond to two prior doses [42 previously exposed to anti‐CD20 monoclonal antibodies (moAbs) including 13 under maintenance treatment]. Seroconversion was obtained in 29.5% of the patients. Longer time from last anti‐CD20 moAb (>6 months) and diagnosis of aggressive lymphoma compared to other, incurable B‐NHLs were associated with increased seroconversion rates (47.8% vs.10.5%, p = 0.019 and 50% vs. 17.9%, p = 0.025 respectively). Thus, seronegative patients with B‐NHL that completed anti‐CD20 therapy more than 6 months prior to the booster have greater chances to achieve seroconversion. [ABSTRACT FROM AUTHOR]

Purpose: The introduction of CD19-specific chimeric antigen receptor T-cell therapy (CAR-T) for treatment of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) gives hope to patients with otherwise dismal prognosis. Therapy outcomes, however, depend upon selection of patients and accurate early identification of non-responders. Patients treated with CAR-T usually undergo [18F]FDG PET-CT at time of decision (TD), time of CAR-T transfusion (TT), 1 month (M1), and 3 months (M3) post-therapy. The purpose of the current study was to identify the specific parameters that should be addressed when reporting PET-CT studies in the clinical setting of CAR-T therapy. Methods: A total of 138 PET-CT scans (30 TD, 42 TT, 44 M1, 22 M3) of 48 patients treated with CAR-T were included. SUVmax, TMTV, and TLG were calculated in all scans. Response was assessed using the Deauville scale and ΔSUVmax method. Overall survival (OS) was the primary endpoint. Median follow-up was 12.8 (IQR 6.4–16.0) months from CAR-T infusion. Results: In a univariate analysis, TD-SUVmax > 17.1 and TT-SUVmax > 12.1 were associated with shorter OS (Pv < 0.05). In a multivariate analysis, three factors were significantly associated with shorter OS: TD-SUVmax > 17.1 (HR 10.3; Pv < 0.01), LDH > 450 U/l (HR 7.7; Pv < 0.01), and ECOG score > 1 (HR 5.5; Pv = 0.04). Data from TD and TT PET-CT scans were not predictive of toxicity. On M1-PET-CT, patients with a Deauville score > 3 had significantly shorter OS (median 7.9 months, versus not reached, Pv < 0.01). ΔSUVmax ≤ 66% on M1-PET-CT predicted shorter OS when M1-SUVmax was compared to TD-SUVmax (Pv = 0.02) but not to TT-SUVmax (Pv = 0.38). Conclusion: Pre-treatment SUVmax may guide patient selection for CAR-T therapy. On M1-PET-CT, Deauville score and ΔSUVmax from TD may identify early therapy failure. These parameters are easy to obtain and should be included in the PET-CT report. [ABSTRACT FROM AUTHOR]

The characteristics of infections following chimeric antigen receptor T (CAR‐T) cells targeting CD19 in real‐word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B‐cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR‐T cells. ECOG performance status (PS) was 2‐3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram‐negative rod, n = 5; Gram‐positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti‐CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell‐associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P =.018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P =.074). Age or PS was not associated with increased risk of bacterial infection. Increase in C‐reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR‐T‐cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma (MM) patients are at excess risk for clinically significant COVID19 infection. BNT162b2 mRNA COVID19 (BNT162b2) vaccine provides effective protection against COVID19 for the general population, yet its effect in MM patients may be compromised due to disease and therapy‐related factors and was not yet evaluated. This single‐centre prospective study included MM patients tested for serological response 14–21 days post second vaccine. Vaccinated healthy volunteers served as controls. In all, 171 MM patients, median age 70 (38–94) were included; 159 active MM and 12 smouldering myeloma (SMM). Seropositive response rate (median titer) was 76% (91 U/ml) in active MM patients vs 98% (992 U/ml) in the 64 controls (P < 0·0001), and 100% (822 U/ml) in SMM patients. Multivariate analysis revealed older age (P = 0·009), exposure to ≥4 novel anti‐myeloma drugs (P = 0·02) and hypogammaglobulinaemia (P = 0·002) were associated with lower response rates. None of the novel agents significantly decreased response rate, whereas daratumumab trended towards reduced response (P = 0·08). Adverse events occurred in 53% and 55% of the MM patients and controls, respectively, all transient grade 1–2. In conclusion, BNT162b2 vaccine was safe and provided a high seropositivity rate in MM patients, independent of treatment type. Older, hypogammaglobulinaemic and heavily pretreated patients had lower response rates. [ABSTRACT FROM AUTHOR]

Purpose: Vaccine-associated hypermetabolic lymphadenopathy (VAHL) is frequently observed on [18F]FDG PET-CT following BNT162b2 administration. Recent data suggest a prominent B cell germinal-center (GC) response elicited by mRNA vaccines in draining lymph nodes. Thus, in this study we aimed to explore the correlation between VAHL and humoral immunity as reflected by post-vaccination serologic testing and by comparing the incidence of VAHL between lymphoma patients treated recently with B cell depleting therapy and those that were not. Methods: A total of 137 patients with hematologic malignancy that had post-vaccination [18F]FDG PET-CT were included (All-PET group), 86 received both vaccine doses before imaging (PET-2 group). Their VAHL status and grade on imaging were recorded. Among 102 lymphoma patients, 34 (33.3%) were treated during the year prior vaccination with anti-CD20 antibody containing therapy. A subgroup of 54 patients also underwent serologic testing 2–3 weeks after the booster dose, and their anti-spike titers were recorded and graded as well. Results: The overall incidence of VAHL in patients with hematologic malignancy was 31.4%. The 34 lymphoma patients treated during the year prior vaccination with anti-CD20 antibody containing therapy had significantly lower rates of VAHL comparted with all other lymphoma patients (8.8 versus 41.2% in all-PET patients, Pv < 0.01). VAHL rates were 10% in patients with negative serology, 31.3% in patients with low anti-spike titers, and 72.2% in patients with high anti-spike titers. The positive predictive values of VAHL were 90 and 93.3% in all-PET and PET-2 patients, respectively. A positive statistically significant correlation was found between VAHL and serology ranks in All-PET patients (rs = 0.530, Pv < 0.001), and stronger correlation was found in PET-2 patients (rs = 0.642, Pv < 0.001). Conclusion: VAHL on [18F]FDG PET-CT of patients with hematologic malignancy may reflect GC B cell proliferation and an effective humoral response elicited by BNT162b2 vaccine. [ABSTRACT FROM AUTHOR]

: ObjectiveHematopoietic stress responses involve increases in leukocyte and platelet counts, implying the existence of stress responsive factors that modulate hematopoiesis. Acetylcholinesterase (AChE) is expressed in mammalian neurons and hematopoietic cells. In brain, it responds to stress by mRNA overexpression and alternative splicing, yielding the rare stress-associated “readthrough” AChE-R variant protein. This led us to explore the hematopoietic involvement of AChE-R and its cleavable C-terminal peptide ARP.: Materials and MethodsAChE mRNA variants were labeled in CD34+ hematopoietic progenitor cells by in situ hybridization. ARP expression was detected by multicolor flow cytometry. Bromo-deoxyuracil incorporation and viable cell counts served to evaluate the proliferative effects of ARP and suppressive effects of the AChE antisense oligonucleotide AS1 on CD34+ cells.: ResultsThe distal enhancer, proximal promoter, and first intron of the human AChE gene include consensus binding sites for hematopoietically active and stress-induced transcription factors. CD34+ cells from human cord blood were found to express all three variant AChE mRNAs, having different intracellular distributions. ARP was found in 5 to 15% of adult peripheral blood, bone marrow, and fetal CD34+ cells (both committed CD38+ and uncommitted CD38−) and in acute myeloid leukemia blasts. Externally supplied ARP by itself facilitated the proliferation of CD34+ cells in an antisense suppressible manner. When combined with early-acting cytokines, ARP enhanced survival and expansion of CD34+ cells up to 28 days in culture.: ConclusionOur findings support ARP, the C-terminal peptide of AChE-R, as a new hematopoietic growth factor that may promote the myelopoietic expansion and thrombopoiesis characteristic of stress and may be used to enhance the efficiency of ex vivo expansion for bone marrow transplantation. [Copyright &y& Elsevier]

The article reports that A 23-year-old female with refractory diffuse large B-cell lymphoma was referred to chimeric antigen receptor T-cell (CAR-T) therapy (axicabtagene ciloleucel). Before infusion, FDG PET-CT (A) identified active supra-diaphragmatic nodal and hepatic disease (SUVmax 14.5). Nine days following infusion, enlarged cervical masses were palpated and the patient complained of worsening dyspnea.

aimed to assess whether the adoption of precautionary measures provided by the medical team led to a reduction in COVID-19-related anxiety and, consequently, to successful execution of treatment plans. Methods: All adult hemato-oncology patients actively treated or being followed-up at the outpatient service at Tel Aviv Sourasky Medical Center between March 25 and May 3, 2020, were invited to answer a questionnaire that focused on their anxiety and adherence to treatment following new measures to reduce risk of infection during the first COVID-19 outbreak. Results: One hundred and fifty patients (representing 24% of those being approached), average age 67 years, 52% male, and 57% undergoing antineoplastic therapy, responded to the survey. The introduction of precautionary measures resulted in a significant reduction in anxiety level in all patients, irrespective of age, sex, or treatment status. Attendance to scheduled visits in day care and outpatient clinics remained unchanged. Adherence to planned blood and imaging tests were 81% and 73%, respectively, and 93% of the patients were satisfied with their medical care. Thirty-two percent of patients used telemedicine. Satisfaction with telemedicine was highest among non-actively treated patients and those experiencing high anxiety levels. Conclusion: Reorganization of the hemato-oncology unit and provision of information to patients reduced COVID-19-related anxiety and enabled the same delivery of therapy as that prior to the pandemic. [ABSTRACT FROM AUTHOR]

Keywords: obinutuzumab; AIHA; ITP; CLL EN obinutuzumab AIHA ITP CLL e1 e4 4 12/21/20 20210101 NES 210101 Obinutuzumab is a type II, glycoengineered, humanized anti-CD20 monoclonal antibody, with enhanced direct cell death and antibody-dependent cell-mediated cytotoxicity.1 Obinutuzumab is FDA-approved for chronic lymphocytic leukaemia (CLL) in combination with chlorambucil, ibrutinib or venetoclax as a first-line treatment.2-4 Similar to rituximab, obinutuzumab induces B-cell depletion and reduced antibody production, granting it the potential to effectively treat antibody-mediated autoimmune phenomena. We report here a retrospective analysis of eight patients with CLL/small lymphocytic lymphoma (SLL) who were treated with single-agent obinutuzumab for autoimmune haemolytic anaemia (AIHA) or immune thrombocytopenia (ITP), from September 2018 to March 2020. Among our patients, the results achieved with obinutuzumab were especially impressive in a patient with ITP, resistant to multiple therapies, including splenectomy and rituximab, who rapidly responded to obinutuzumab. A prospective randomized trial comparing the efficacy of obinutuzumab and rituximab in the treatment of AIHA/ITP in patients with CLL/SLL, as well as the optimal duration of treatment (e.g. short-term obinutuzumab), is warranted. [Extracted from the article]

Hodgkin lymphoma (HL), a disease of mostly young patients, also peaks in the elderly. Despite the profound improvement in the outcome of young patients, in the elderly, 5-year progression-free survival (PFS) rates are under 70%. Interim PET-CT (iPET) is known to be highly predictive for PFS in young HL patients, but it has not been sufficiently validated in the elderly patient population. In this multi-center collaboration, all consecutive elderly patients (age ≥ 60) diagnosed with HL between 1998 and 2016 were retrospectively reviewed. Baseline characteristics, outcome measures, and iPET results, classified according to the Deauville score, were recorded and analyzed. We identified 78 elderly HL patients (median age 69) who underwent iPET. ABVD was the treatment regimen in 52 (67%) patients. Eighty-three percent of patients had iPET scores of 1-3 while 17% had scores of 4-5. Patients with iPET scores of 1-3 had 5-year PFS and OS rates of 72% and 82% compared with 25% and 45%, respectively, in patients with scores of 4-5 (p < 0.001). Our findings show that iPET is highly predictive of outcome in elderly HL patients and provide evidence that iPET-guided therapy in this patient population may be key to achieving superior treatment outcome. [ABSTRACT FROM AUTHOR]

The article presents a study on the use of the mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitor in analyzing chronic lymphocytic leukemia (CLL) cells. It notes that studied CLL cells were taken from patients' blood samples. A chart is presented on the Mi-2 apoptosis in CLL cells.

Hodgkin lymphoma (HL) is one of the most curable malignancies. Despite its effectiveness, chemotherapy is often associated with adverse events (AEs) such as nausea, anorexia, and impairment of general well-being. Our objective was to assess the extent of medical cannabis use among HL patients and evaluate its efficacy in controlling chemotherapy-related AEs. Patterns of medical cannabis use and efficacy were evaluated using physician-completed application forms, medical files, and patient-completed questionnaires, for all consecutive adult HL patients treated at the Tel-Aviv Medical Center between June 2010 and November 2016. One-hundred and thirty-three patients met the inclusion criteria. The median age of the cohort was 37 years, 53% were male, 46% were diagnosed at an early stage, and 88% achieved a complete response to treatment. Fifty-one patients (38%) used medical cannabis. There were no significant differences in baseline characteristics between cannabis users and nonusers. Cannabis users reported improvement in pain, general well-being, appetite, and nausea in 94, 87, 82, and 79% of cases, respectively. Importantly, 81.5% reported a high overall efficacy of cannabis in relieving symptoms. AEs related to cannabis use itself were mild. Thus, medical cannabis use is prevalent in this HL cohort, and appears to be effective in ameliorating chemotherapy-related AEs. [ABSTRACT FROM AUTHOR]

Patients with diffuse large B-cell lymphoma (DLBCL) presenting with intestinal involvement are prone to develop perforation. Identification of those who are at high risk for this complication would enable a rational-based decision regarding preemptive surgery. Although computed tomography (CT) is widely used at diagnosis, data regarding its ability to predict intestinal perforation are scanty. We performed a retrospective single-center study, including all consecutive DLBCL patients presented with intestinal involvement, assessing predictors for perforation with an emphasis on CT-related parameters. Forty-nine patients were included, 43 (88%) underwent CT scan at diagnosis. Ten patients (20%) developed intestinal perforation. A univariate regression analysis found increased risk among patients with a concentric, transmural lesion, and a longer involved intestinal segment. In conclusion, CT scan results can define patients with DLBCL and intestinal involvement who are at risk for perforation, suggesting that a preemptive surgical resection should be considered in these cases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article presents several case studies related to flow Cytometry-based Detection of B-cell Lymphoproliferative Disorders in Patients with Mycosis Fungoides. Topics discussed a 61-year-old man was referred for evaluation of a non-pruritic rash that initially involved abdomen and later progressed to the back and limbs, and 59-year-old woman presented with a pruritic rash distributed over lateral aspects of her back and axilla with findings compatible with early-stage MF histopathologically.

Keywords: ibrutinib; direct oral anticoagulants; bleeding risk EN ibrutinib direct oral anticoagulants bleeding risk e31 e33 3 04/15/20 20200415 NES 200415 Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, is an established therapeutic agent in a variety of B-cell lymphoproliferative disorders. However, risk of bleeding is not negligible, and treatment resumption in patients that experienced a significant bleeding event should be considered with caution. [Extracted from the article]

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. Patients with stage I disease are usually treated with radiotherapy (RT). In previous studies, mostly from the pre positron emission tomography-computed tomography (PET-CT) era, the 5 year progression-free survival (PFS) and overall survival (OS) rates of stage I disease were 60-80% and 80-93%, respectively. This study retrospectively evaluated the outcome of stage I FL which was treated with involved field RT in the PET-CT era between 2002 and 2015. Ninety-one patients were enrolled. Five year PFS and OS rates were 73% and 97%, respectively. Relapse occurred in 19 (21%) patients, 74% occurring outside the radiation field. In conclusion, PET-CT staging of clinical stage I FL may contribute to the improved prognosis in patients treated with RT compared to historical cohorts, possibly due to better identification of “genuine” stage I disease. [ABSTRACT FROM AUTHOR]

Background Relatives of patients with chronic lymphocytic leukemia ( CLL) are at increased risk of developing CLL. Familial CLL is defined as more than one case of CLL among blood relatives, a phenomenon reported in approximately 5%-10% of all CLL patients. Objective Given the known predisposition of CLL among Ashkenazi Jews, we studied the features of familial CLL in an Israeli population. Methods This is a retrospective study, in which we reviewed the demographics, clinical characteristics, and outcomes of a total of 332 patients with CLL/small lymphocytic lymphoma. Results Familial CLL was recorded in 41 cases (12.3%) of the patients. The age at diagnosis was younger in patients with familial CLL (by almost 3.5 years). Familial CLL was strongly associated with Ashkenazi Jewish origin. Patients with familial CLL more commonly presented with higher hemoglobin and lower serum β-2-microglobulin levels. No significant differences were detected between sporadic and familial CLL in disease stage, time to treatment, second cancers, or overall survival. Conclusion Familial cases of CLL in an Israeli population show a disproportionate ethnic distribution toward Jews of Ashkenazi origin. The clinical characteristics and the overall outcome are not substantially different from sporadic cases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The recent surge in coronavirus disease 2019 cases led to the consideration of a booster vaccine in previously vaccinated immunosuppressed individuals. However, the immunogenic effect of a third-dose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in immunosuppressed patients is still unknown. This was an observational cohort study of 279 previously vaccinated immunosuppressed patients followed at a single tertiary hospital in Israel. Patients were administered a third dose of the Pfizer-BioNTech mRNA vaccine (BNT162b2) between July 14 and July 21, 2021. Levels of IgG antibodies against the spike receptor-binding domain of SARS-CoV-2 were measured 3 to 4 weeks after vaccination. Of the cohort of 279 patients, 124 (44.4%) had haematologic malignancies, 57 (20.4%) had rheumatologic diseases, and 98 (35.1%) were solid organ-transplant recipients. Anti–SARS-CoV-2 antibody levels increased in 74.9% of cases. Across the entire cohort, the median absolute antibody levels (expressed in AU/mL) increased from 7 (interquartile range (IQR), 0.1–69) to 243 (IQR, 2–4749) after the booster dose. The response significantly varied across subgroups: The transplant cohort showed the greatest increase in absolute antibody levels (from 52 (IQR, 7.25–184.5) to 1824 (IQR, 161–9686)), followed by the rheumatology (from 22 (IQR, 1–106) to 1291 (IQR, 6–6231)) and haemato-oncology (from 1 (IQR, 0.1–7) to 7.5 (IQR, 0.1–407.5)) cohorts. The χ2 test was 8.30 for difference in fold change (p = 0.016). Of the 193 patients who were seronegative at baseline, 76 became seropositive after vaccination, corresponding to a 39.4% (95% CI, 32.8%–46.4%) seroconversion rate. Transplant patients had the highest seroconversion rate (58.3% (95% CI, 44.3%–71.2%)), followed by rheumatology (44.1% (95% CI, 28.9%–60.5%)) and haemato-oncology (29.7% (95% CI, 22%–38.8%); χ2 = 11.87; p = 0.003) patients. A third dose of BNT162b2 is immunogenic in most immunosuppressed individuals, although antibody response may differ based on the type of disease and immunosuppression. The antibody level that correlates with protection is still unknown; thus, future studies are needed to evaluate clinical outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Automated morphological assessment of peripheral blood slides has become an important modality facilitating characterization and quantification of cells in a uniform, fast and robust manner. In this study, we evaluated the morphological diversity in peripheral blood films of 94 chronic lymphocytic leukemia (CLL) patients using the DM1200 CellaVision automated microscopy system. Aberrant lymphocytes and smudge cells were enumerated and correlated with CLL immunophenotype, chromosomal aberrations and prognostic parameters. Herein, we show that the percentages of aberrant and smudge cells was highly variable between patients and did not correlate with each other. Increased aberrant lymphocytes and fewer smudge cells were associated with an atypical immunophenotype including low expression of CD23, higher levels of FMC7 and bright surface levels of CD20. High fraction of aberrant lymphocytes also was associated with trisomy 12. These cells were predominantly of small/medium size, sometimes with cleft nuclei. No correlation was noted between aberrant or smudge cells and clinical stage, CD38, ZA70 or time to first treatment. Taken together, automated morphological analysis of peripheral blood leukocytes emerged as a powerful and robust tool for the quantitative morphological stratification of CLL. Integration of the automated morphological features discriminates between different CLL phenotypes and distinct chromosomal aberrations. [Copyright &y& Elsevier]

Abstract: Peripheral absolute monocyte count (AMC) has been reported to correlate with clinical outcome in different types of cancers. This association may relate to alteration in circulating monocytic subpopulations and tumor infiltrating macrophages. In this study we evaluated the clinical significance of peripheral AMC in 80 treatment naive patients with CLL. Measurement of AMC was based on direct morphological enumeration, due to our findings that complete blood count data may yield incorrect monocytes enumeration values in CLL. The median AMC in patients with CLL was within normal limits, however the AMC range exceeded the values of healthy individuals. The AMC trichotomized patients into 3 distinct sub-groups with different characteristics and outcomes. High AMC patients were younger and had higher absolute lymphocytes count, while patients with low AMC had prominent immune dysregulation (lower serum IgA levels, susceptibility to infections and a tendency for positive direct anti-globulin test). The low and high AMC patients had a shorter time to treatment compared to the intermediates AMC subgroups, whereas low AMC was associated with increased mortality caused by infectious complications. In conclusion, AMC quantification during the disease course classifies CLL patients into subgroups with unique clinical features and outcomes. [Copyright &y& Elsevier]

Emerging data on intraclonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. In this study, we report intraclonal diversity resolved by responses to CD 19 engagement in CLL cells, which can be classified into CD19-responsive (CD19-R) and -nonresponive subpopulations. Engagement of CD19 by anti-CD19 Ab rapidly induced cellular aggregation in the CD19-R CLL cells. The CD19-R CLL cells expressed higher surface levels of CD19 and c-myc mRNA, exhibited distinct morphological features, and were preferentially abolished in rituximab-treated patients. Both subpop-ulations reacted to slgM stimulation in a similar manner and exhibited similar levels of Akt and Erk phosphorylation, pointing to functional signaling divergence within the BCR. CD19 unresponsiveness was partially reversible, where nonresponding CD19 cells spontaneously recover their signaling capacity following incubation in vitro, pointing to possible in vivo CD19-signaling atten-uating mechanisms. This concept was supported by the lower CD19-R occurrence in bone marrow-derived samples compared with cells derived from the peripheral blood of the same patients. CLL patients with >15.25% of the CD19-R cell fraction had a shorter median time to treatment compared with patients with <15.25% of CD19-R cell fraction. In conclusion, divergence in CD19-mediated signaling unfolds both interpatient and intraclonal diversity in CLL. This signaling diversity is associated with physiological implications, including the location of the cells, their responses to anti-CLL therapeutics, and disease progression. [ABSTRACT FROM AUTHOR]