Diagnosis Of Chronic Lymphocytic Leukemia Research Articles

Chronic Lymphoid Leukemia: a systematic review of its epidemiological, etiological and genetic aspects

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative neoplasm that mainly affects the elderly, being the most common leukemia in western adults. It is estimated the presence of about 191,000 new cases annually in the world. Despite the advances made in the diagnosis and therapeutic management of CLL, its etiological and genetic aspects are still not completely clear. The objective of the article was to address and bring together the main epidemiological and etiopathogenic aspects of CLL, exploring how a greater biological understanding of the disease can improve and generate new therapeutic strategies.

The 'inbetweeners': living on a watch and wait approach for chronic lymphocytic leukaemia - a qualitative study.

Chronic lymphocytic leukaemia (CLL) is an incurable disease; many people with the condition do not require active treatment and are monitored using a watch and wait approach. The aim of this study was to explore the experiences of people living with a diagnosis of CLL and on watch and wait. Using a descriptive qualitative approach, seven participants on the watch and wait approach were interviewed. Data analysis was guided by systematic text condensation. Participants reported anxiety, referring to 'wait and worry'. Their information needs were not met, and they resorted to seeking information on possible future treatments themselves. They also experienced feeling like an imposter because they were not receiving active treatment like other patients with cancer. A greater understanding of how information provision affects levels of anxiety and worry among people living with CLL on watch and wait is needed. In addition, clinical nurse specialists could deliver education on the watch and wait approach, supplemented by video-based educational materials developed by the haematology team.

232 Skin Cancer Histopathology Requests Within a Plastic Surgery Service

Abstract Aim To ascertain whether plastic surgeons include adequate information on skin cancer histopathology request forms to aid accurate and timely histopathological diagnosis. Method We completed a prospective closed loop audit on histopathology request documentation at a single centre over two two-week periods. The standards were agreed following multi-disciplinary discussion (dermatology, plastic surgery, and pathology) and based on the Royal College of Pathology dataset. Mandatory information was differentiated from desirable information. A poster intervention was introduced that illustrated the guidance. Inclusion criteria consisted of excision biopsies and wide local excisions performed under local anaesthetic in minor operating rooms. Results Pre-intervention data included 45 lesions excised from 33 patients. A description of the lesion was documented in 26%, provisional diagnosis in 91%, lesion progression in 11%, surgical margins at the periphery in 56%, margins at deep in 16% and relevant past medical history (previous chronic lymphocytic leukaemia diagnosis and previous radiotherapy on that site) in 9%. Post-intervention data included 45 lesions from 40 patients. There was improved compliance with all standards. A description of the lesion was documented in 76%, provisional diagnosis in 98%, lesion progression in 33%, margins at the periphery in 78%, margins at deep in 38% and relevant past medical history in 29%. Site and laterality were documented in all patients in both cohorts. Conclusions We observed improved documentation following a simple educational intervention. Further studies should aim to understand the impact this has on laboratory turnaround times, and further improve adherence to agreed guidance by incorporating mandatory fields in the request form.

Secondary Thyroid Lymphoma Due to Chronic Lymphocytic Leukaemia (CLL)

Introduction: Thyroid lymphomas are a rare finding among thyroid malignancies, and Chronic Lymphocytic B-cell (CLL-B) type of thyroid lymphoma is even more infrequent. Lymphomas compose only 2% of thyroid malignancies, with primary thyroid lymphomas constituting only 2.5% of all lymphomas. Chronic lymphocytic B-cell (CLL-B) type of thyroid lymphoma (CLL-B) is is exceptionally rare, with only 4% of cases ever reported worldwide. Case Presentation: A 55-year-old female presented with a complaint of swelling over the anterior part of neck. She had a pre-existing diagnosis of CLL, fine needle aspiration biopsy (FNAB)of the swelling revealed lymphocytic proliferation, classified as Bethesda grade II. The patients was in a euthyroid state and a ‘core-needle’ biopsy was performed to confirm the diagnosis of lymphocytic infiltration of the thyroid. The patient was managed conservatively and is currently under regular follow-up. Conclusions: The occurrence of thyroid swelling in CLL is a rare phenomenon, and confirming the diagnosis through biopsy is recommended. Surgeons should be cautious not to be deceived by the rarity of the swelling and avoid unnecessary surgical interventions. Conservative management has been the prevailing approach in the literature. This case report serves to support this conservative approach and contributes to the existing literature on Thyroid lymphoma due to CLL.

Genetic drivers in the natural history of chronic lymphocytic leukemia development as early as 16 years before diagnosis

Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a potential CLL precursor state which can be detected in up to 17% in aged individuals. Recently, we described significant B-cell receptor immunoglobulin heavy chain (BCR IGH) gene repertoire skewing and clonotypic evolution up to 22 years before CLL diagnosis. However, pathobiological drivers during the earliest stages of MBL development remain incompletely characterized. In this study, we utilized the EuroClonality-NDC panel to sequence recurrently mutated genes in CLL in 39 peripheral blood samples from 16 CLL patients sampled up to 16 years prior to diagnosis. CLL diagnosis ranged from 5 months to 16 years after first blood sampling. Of 16 CLL patients, 8 (50%) presented with variants of interest in genes recurrently mutated in CLL such as NOTCH1, ATM, and SF3B1 . ATM variants and the IGLV3-21R110 mutation were present from the early stages of (pre)MBL development, while NOTCH1, SF3B1, and XPO1 variants arose closer to diagnosis. We additionally detected variants in FAT1 and PLCG2 as early as 10 years prior to CLL diagnosis. Overall, our data shows specific genetic drivers of CLL are associated with early and late stages of CLL development.

Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia

Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N= 24; US-Mayo Clinic, N= 15; AUS, N= 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P= 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Update on diagnosis and treatment of Chronic Lymphocytic Leukemia (CLL)

commonest leukemia found in adults western countries, affects more than 200000 people and is associated with approximately 4410 death in the USA annually. CLL is characterized by a progressive proliferation and accumulation of mature yet functionally incompetent lymphocytes. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B-cells. Diagnosis: The diagnosis of chronic lymphocytic leukemia (CLL) requires the presence of more than or equal to 5 × 109/L B lymphocytes (5000/μL) in the peripheral blood for the duration of at least 3 months. Immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen, as well as typical B-cell markers are confirmatory test. Prognosis: The two similar clinical staging systems, Binet and Rai stages, create prognostic information by using results of physical examination and blood counts. Various molecular biology markers also have prognostic value. Mutations of the TP53 gene and x chromosome 17 chromosome (del [17p) predict resistance to chemoimmunotherapy and a shorter time to progression, with most targeted therapies. A comprehensive, international prognostic score (CLL-IPI) integrates genetic, biological and clinical variables to identify distinct risk groups of CLL patients. Therapy: Early-stage disease of CLL patients are followed up regularly, only patients with active or symptomatic disease or with advanced stages of Binet or Rai require treatment. When treatment is indicated, most patients with CLL have several options: a combination of obinutuzumab and venetoclax, ibrutinib monotherapy, or immunochemotherapy. In patients under 65 years of age who are physically fit (particularly if they have a mutated IGVH gene), immunochemotherapy with fludarabine, cyclophosphamide, and rituximab remains the standard of care because of its potential therapeutic potential. In case of relapse, the initial treatment can be repeated if the treatment-free period exceeds 3 years. And in case of early recurrence of the disease, treatment should be switched to an alternative regime. Patients with del(17p) or TP53 mutations are another high-risk group and should be treated with targeted drugs. Allogeneic SCT can be considered in patients with TP53 or del(17p) mutations or in patients on inhibitor therapy.

Treatment with idelalisib in patients with chronic lymphocytic leukemia – real world data from the registry of the German CLL Study Group

Idelalisib in combination with rituximab is an efficacious treatment for patients suffering from chronic lymphocytic leukemia (CLL) with known limitations due to toxicities. However, the benefit after prior Bruton tyrosine kinase inhibitor (BTKi) therapy remains unclear. For this analysis, 81 patients included in a non-interventional registry study of the German CLL study group (registered at www.clinicaltrials.gov as # NCT02863692) meeting the predefined criteria of a confirmed diagnosis of CLL and being treated with idelalisib containing regimens outside clinical trials were considered. 11 patients were treatment naïve (13.6%) and 70 patients (86.4%) pretreated. Patients had median of one prior therapy line (range 0–11). Median treatment duration with idelalisib was 5.1 months (range 0–55.0 months). Of 58 patients with documented treatment outcome, 39 responded to idelalisib containing therapy (67.2%). Patients treated with the BTKi ibrutinib as last prior treatment prior to idelalisib responded in 71.4% compared to a response rate of 61.9% in patients without prior ibrutinib. Median event free survival (EFS) was 15.9 months with a 16 versus 14 months EFS in patients with ibrutinib as last prior treatment or not, respectively. Median overall survival was 46.6 months. In conclusion, treatment with idelalisib appears to have a valuable impact in patients being refractory to prior ibrutinib therapy even though there are limitations in our analysis due to the low number of patients included.

A population level analysis of second hematological malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma survivors in the era of targeted therapies.

With improvement in survival after chronic lymphocytic leukemia (CLL) diagnosis, the real-world burden of second hematological malignancies (SHM) has not been comprehensively assessed in recent era. We analyzed risk, incidence, and outcomes of SHM in CLL patients between 2000 and 2019 using SEER database. CLL patients had greater risk for hematological malignancies than general population [SIR, standardized incidence ratio (95% CI):2.58 (2.46-2.70); p<0.05]. The risk for subsequent lymphoma increased by 1.75 folds in 2015-2019 compared to 2000-2004. The duration, after CLL diagnosis, of maximum risk for SHM decreased as 60-119months for time-period 2000-2004, 6-11months for 2005-2009 to 2-5months for 2010-2014 and 2015-2019. Incidence of SHM was 2.5% in CLL survivors (1736/70,346) with lymphoid SHM being more common than myeloid SHM, and DLBCL being the most common pathology (n=610, 35% of all SHM). Male sex, age ≤65years at CLL diagnosis, and chemotherapy treatment were associated with higher risk for SHM. The median gap between CLL and SHM diagnoses was 46months. The median survival for de-novo-AML, t-MN, CML, and aggressive NHL was 63, 86, 95, and 96months respectively. Although SHM remains rare, there is increased risk in recent era, likely due to improved survival in CLL patients, necessitating active surveillance strategies.

A study of frontline therapy in adults &gt;80 years with chronic lymphocytic leukemia (CLL).

12057 Background: AlthoughCLL primarily affects older adults (median age 71 years), limited data exists about the outcomes of adults who are ≥80 years old because they are under-enrolled on clinical trials. Methods: The Mayo Clinic CLL Database was used to conduct a retrospective cohort study of adults ≥80 years at the time of frontline CLL treatment. Kaplan-Meier analysis was used to plot OS, and cumulative incidence was used to plot TTNT, accounting for competing risk of death. The Mayo Clinic IRB approved the study. Results: Our study included 216 patients with CLL who were age ≥80 years at the time of frontline CLL therapy between 1/1995 and 11/2022 (Table). The median time from CLL diagnosis to initiation of frontline therapy was 3.1 years. The median OS after start of frontline therapy was 3.9 years. The median OS was 3.3 years (95% CI 2.6–4.2) for patients who received alkylating agents (e.g., chlorambucil, n=96), 3.8 years (95% CI 2.8–not reached [NR]) for purine analogues (e.g., fludarabine, n=11), 3.9 years (95% CI 3.2–4.9) for anti-CD20 monoclonal antibody monotherapy (e.g., obinutuzumab, n=64), and not reached (95% CI 3.3-NR) for novel agents (n=43) (P=0.02). The types of novel agents included ibrutinib (n=19), acalabrutinib (n=16), venetoclax (n=7), and orelabrutinib (n=1). There was no difference in OS between 36 patients who received a BTKi compared to the 7 patients who received venetoclax-based therapy. At a median follow-up time of 6.7 years from the first visit, 143 patients died from the following: progressive CLL (n=63), infections (n=12), other cancer (n=11), non-CLL reasons (n=21). Cause of death was unavailable for 36 patients. On multivariable analyses, older age (i.e., any 5-year increase in age) was associated with a 50% increased risk of death (HR 1.5, 95% CI 1.2-1.9, p=0.001), and treatment with non-novel agents was associated with 3.2 times increased risk of death (HR 3.2, 95% CI 1.2-8.9, p=0.02). Of the 216 patients, 76 patients required second-line therapy; the median TTNT was 4.2 years (95% CI 2.9-NE). The most used second-line agents were monoclonal antibodies alone (20/76, 26%) and single-agent alkylators (18/76, 24%). Conclusions: When compared to all other CLL treatments, novel agents such as BTKi and venetoclax-based treatments are associated with significantly improved OS in patients with CLL ≥80 years old when used in the frontline setting. [Table: see text]

Impact of type 2 diabetes on mortality, cause of death, and treatment in chronic lymphocytic leukemia.

Age-related comorbid conditions are exceedingly common in patients with chronic lymphocytic leukemia (CLL). As the prevalence of type 2 diabetes (T2D) is predicted to double during the next two decades, a better understanding of the interplay between CLL and T2D is of increasing importance. In this study, analyses were performed in parallel in two separate cohorts, based on Danish national registers and the Mayo Clinic CLL Resource. The primary outcomes were overall survival (OS) from time of CLL diagnosis, OS from time of treatment, and time to first treatment (TTFT), studied using Cox proportional hazard regression analysis and Fine-Gray regression analysis. In the Danish CLL cohort, the prevalence of T2D was 11%, in the Mayo CLL cohort, it was 12%. Patients with CLL and T2D had shorter OS both from time of diagnosis and from first-line treatment for were less likely to receive treatment for CLL compared with patients with CLL and without T2D. The increased mortality was largely driven by an increased risk of death due to infections, especially in the Danish cohort. The findings of this study emphasize a substantial subgroup of CLL patients with co-occurring T2D with an inferior prognosis and a possible unmet treatment need requiring additional interventions and further research.

Invasion of chronic lymphocytic leukemia (cll/sll) bloodstream tumor cells by borrelia spirochetes

A sixty-six-year-old woman with a strong family history of breast cancer noted gradual onset of axillary lymph node enlargement in 2019. Axillary lymph node biopsies disclosed Lymph node involvement by Chronic Lymphocytic Leukemia (CLL/SLL). Immunophenotype analysis of nodal tissue and of bloodstream leukemic cells in immunohistochemistry and flow cytometry and next generation molecular diagnostics confirmed CLL/SLL. Replicate absolute peripheral blood lymphocyte counts in excess of 5.0x10e3/microliter confirmed the numerical threshold for diagnosis of Chronic Lymphocytic Leukemia in the bloodstream. FISH studies disclosed an immunoglobulin “mutation negative” CLL/SLL genotype without a light chain restriction pattern. No translocations or germline mutations were present. Borrelia spirochetes in the bloodstream were detected with simultaneous high spirochetemia of both borrelia miyamotoi and borrelia burgdorferi. FISH hybridization of leukemic lymphocytes disclosed extensive borrelia invasion of the cytoplasm and of the nucleus compartments of CLL/SLL tumor cells. Retrospective studies of the patient’s archival stored blood smears obtained three years prior in 2016 at age 63 disclosed no evidence of CLL/SLL but confirmed asymptomatic bloodstream borrelia miyamotoi and borrelia burgdorferi borrelia infection. Lyme serology had been reported as negative in 2016. Additionally, retrospective FISH DNA hybridizations focused on preleukemic bloodstream Lymphocytes disclosed rare borrelia spirochetal adherence to benign blood lymphocytes in the year 2016 in the preleukemic blood smears. This case report is the very first to describe precursor chronic asymptomatic Lyme borreliosis and Miyamotoi borrelia bloodstream infections three years prior to the diagnosis of Rai Stage 1 Chronic Lymphocytic leukemia.

Patterns of IgG Testing and Rates of Hypogammaglobulinemia in Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

BackgroundInfections cause substantial morbidity and up to 50% of deaths in patients with chronic lymphocytic leukemia (CLL). Hypogammaglobulinemia (HGG), a reversible risk factor for severe infections, is associated with CLL and its therapies. We evaluated patterns of immunoglobulin G (IgG) testing and immunoglobulin replacement therapy (IgRT) initiation in patients with CLL. MethodsThis retrospective, longitudinal study evaluated the real-world use of IgG testing in adults with CLL diagnosed after 2010 using deidentified clinical data from the Massachusetts General Brigham Research Patient Data Registry. Eligible patients had ≥12 months of clinical information post-CLL diagnosis and ≥3 visits/year. Timing of IgG testing, IgRT initiation, and serum IgG levels before and after IgRT initiation were examined. Results were reported with descriptive statistics including medians and interquartile range (IQR); P-values were calculated using McNemar’s test. ResultsThe cohort included 2842 patients; median (IQR) age was 69 (60, 76) years, 61.3% were men, 92.9% were White, 75.2% were treatment-naïve, and median (IQR) follow-up was 4.2 (2.2, 6.8) years. Of 1352 (47.6%) patients with IgG testing during the follow-up period, median (IQR) number of IgG tests was 0.5 (0.2,1.2) per patient/year; 34.1% had HGG (IgG < 500 mg/dL). Median (IQR) time from CLL diagnosis to first IgG test was 6.9 (0.9, 22.6) months. Number of IgG tests, IgRT administrations, timing of IgRT initiation from diagnosis and IgG testing, and serum IgG levels before and after IgRT initiation are described in the Table. Among patients with ≥1 IgRT administration, median (IQR) IgG serum levels improved and the proportion of patients with HGG decreased ≥12 months following IgRT initiation (Table). ConclusionsAs CLL treatment evolves, it is important to identify which patients are at greatest risk of infections and to standardize HGG screening. This study demonstrates that IgG levels are not assessed frequently post-CLL diagnosis, nor uniformly reassessed following initiation of IgRT. Among patients with CLL receiving IgRT, IgG levels improved after IgRT initiation. Thus, increased awareness and IgG screening might reduce severe or recurrent infections in the CLL patient population.Takeda Pharmaceuticals USA, Inc. funded the study and writing support.

The role of surgery in perianal disease developing in hematology malignancy patients

Objective: Perianal diseases may impair the comfort of life in immunosuppressive patients as well as cause life-threatening complications. In this study, we aimed to analyze the surgical management and results of perianal region diseases in hematological patients who were consulted by the hematology clinic and to present non-surgical treatment options in these patients. Method: The files of the patients who were consulted by the Hematology Clinic of our hospital between January 2011 and January 2021 due to perianal disease were retrospectively reviewed. Patients with multiple data deficiencies were excluded from the study. Gender, age, hematological diagnosis, neutropenic status, number of consultations, surgical diagnosis, radiological imaging methods, treatment modalities and survival data of the patients were recorded. Results: A total of 911 consultations were requested from 627 patients. The number of patients consulted with the diagnosis of perianal disease was 147. Ninety (61.2%) of the patients were male and 57 (38.7%) were female. Of the patients, 74 (50.3%) had acute myeloid leukemia, 29 (19.7%) lymphoma, 15 (10.2%) acute lymphoblastic leukemia, 12 (8.1%) myelodysplastic syndrome, 10 (6.8%) multiple myeloma, 7 (4.7%) of them were followed up with the diagnosis of chronic lymphocytic leukemia, 53 (36%) patients had additional systemic disease besides hematological disease. All patients were examined and prediagnosed. Magnetic resonance imaging was performed in 72 patients with suspected abscess and fistula. Surgical treatment methods were applied to 30 (20.4%) of the patients. Conclusion: Perianal diseases frequently accompany hematological diseases, especially in neutropenic periods. With early examination, close follow-up and appropriate treatment, surgical necessity and the number of relapsed diseases can be minimized.

Hypophosphatemia related to the use of ibrutinib.

Tyrosine kinase inhibitors (TKis) and Bruton's TKi (BTKis) constitute broadly used antitumor drug groups with almost completely tolerable and manageable side-effect profiles. Mainly side effects are cardiovascular and gastrointestinal for the TKi group. Hypophosphatemia is documented frequently in many studies with TKis but rarely mentioned with ibrutinib use up to the present. A 61-year-old patient with the diagnosis of chronic lymphocytic leukemia had hypophosphatemia-related complaints and symptoms when ibrutinib use was preferred for his second relapse of the disease. After drug discontinuation, we started ibrutinib again with an alternating dose. We managed to control hypophosphatemia, and the patient has been following up for 2 years in remission status without any support or a second drug need. We have presented here a chronic lymphocytic leukemia case that developed mild-severe hypophosphatemia associated with ibrutinib use. By using an alternating dose of ibrutinib, we managed to control the disease and drug side effects. TKis and BTKis are widely in use for different indications. Hypophosphatemia is rare but it can cause drug discontinuation or change if it is not manageable. It is mentioned that hypophosphatemia can be seen due to a common group effect with the mechanism of causing secondary hyperparathyroidism and renal tubulopathy. In our case, we could explain the side effect of hypophosphatemia with secondary hyperparathyroidism and renal tubulopathy. Prospective, large-group studies are needed to explain the hypophosphatemia and other side effects of ibrutinib and new BTKis in detail.

Circular RNA Expression Signatures Provide Promising Diagnostic and Therapeutic Biomarkers for Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a known hematologic malignancy associated with a growing incidence and post-treatment relapse. Hence, finding a reliable diagnostic biomarker for CLL is crucial. Circular RNAs (circRNAs) represent a new class of RNA involved in many biological processes and diseases. This study aimed to define a circRNA-based panel for the early diagnosis of CLL. To this point, the list of the most deregulated circRNAs in CLL cell models was retrieved using bioinformatic algorithms and applied to the verified CLL patients' online datasets as the training cohort (n = 100). The diagnostic performance of potential biomarkers represented in individual and discriminating panels, was then analyzed between CLL Binet stages and validated in individual sample sets I (n = 220) and II (n = 251). We also estimated the 5-year overall survival (OS), introduced the cancer-related signaling pathways regulated by the announced circRNAs, and provided a list of possible therapeutic compounds to control the CLL. These findings show that the detected circRNA biomarkers exhibit better predictive performance compared to current validated clinical risk scales, and are applicable for the early detection and treatment of CLL.

Extensive Central Nervous System Lymphoma Detected at the Time of Diagnosis of Chronic Lymphocytic Leukemia - An Isolated Central Nervous System Richter’s Syndrome: A Case Report

When a central nervous system (CNS) lesion is found in patients with chronic lymphocytic leukemia (CLL), the diagnostic possibilities include CNS involvement of CLL, transformation to a large B-cell lymphoma (Richter’s syndrome [RS]), or the coincidental presence of another tumorous or non-tumorous disease. CNS RS commonly occurs in preexisting CLL with other nodal/extra-nodal involvement, but it is extremely rare to find isolated CNS RS concurrently with the initial diagnosis of CLL. A 73-year-old woman presented with a headache and findings from another hospital of an elevated white blood cell count and intraventricular masses. A peripheral blood smear and a bone marrow biopsy revealed CLL. Brain magnetic resonance imaging with gadolinium enhancement showed a suprasellar mass and a pineal mass within the third ventricle, as well as extensive leptomeningeal enhancement. Whole-body fluorodeoxyglucose proton emission tomography-computed tomography showed no hot uptake except for the brain lesions. Cerebrospinal fluid cytology showed small atypical lymphocytes suggestive of CLL involvement. However, an endoscopic biopsy of the third-ventricle mass demonstrated diffuse large B-cell lymphoma. After 3 months of systemic high-dose methotrexate, all preexisting lesions disappeared, but new hemorrhagic masses were found in the right lateral ventricle and the fourth ventricle. The patient received palliative cranial radiotherapy but died 6 months after the initial diagnosis. Accurate CNS tissue diagnosis and appropriate treatment are critical.

Serological and cellular response to mRNA-SARS-CoV2 vaccine in patients with hematological lymphoid malignancies: Results of the study "Cervax".

messenger RNA (mRNA)-Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccines such as BNT162b2 became available in late 2020, but hematological malignancy patients (HM pts) were not evaluated in initial registration trials. We hereby report the results of a prospective, unicentric, observational study Response to COVID-19 Vaccination in hEmatological malignancies (CERVAX) developed to assess the postvaccine serological and T-cell-mediated response in a cohort of SARS-CoV2-negative HM pts vaccinated with BNT162b2. Patients with lymphomas [non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL)], chronic lymphocytic leukemia (CLL), and multiple myeloma (MM); off-therapy for at least 3 months; in a watch-and-wait program; or in treatment with ibrutinib, venetoclax, and lenalidomide were included. Different time points were considered to assess the serological response to the vaccine: before the second dose (T1), at 3-6-12 months after the first dose (T2-3-4, respectively). Since March 2021, 39 pts have been enrolled: 15 (38%) NHL, 12 (31%) CLL, and 12 (31%) MM. There were 13 of the 39 pts (33%) seroconverted at T1; an increase of the serological response was registered after the second dose (T2) (22/39 pts, 56%) and maintained after 6 months (22/39 pts, 56%) and 12 months (24/39 pts, 61%) from the first dose (T3-T4, respectively). Non-serological responders at T4 were 7/39 (18%): 0/15 NHL, 1/12 MM (8%), and 6/12 CLL (50%). All of them were on therapy (one lenalidomide, three ibrutinib, and three venetoclax). SARS-CoV2-reactive T-cell analysis (interferon gamma release assays) was available since June 2022 and was evaluated at 12 months (T4) from the first dose of vaccine in 31/39 pts (79%). T-cell-mediated-responders were 17/31 (55%): most of them were NHL and MM (47%, 41% and 12% for NHL, MM, and CLL, respectively). Both serological and T-cell non-responders were represented by pts on active therapy (venetoclax/ibrutinib). During the period of observation, eight (20.5%) pts developed mild SARS-CoV2 infection; no coronavirus disease 19 (COVID-19)-related deaths or hospitalizations were registered. In conclusion, in our cohort of lymphoproliferative pts receiving BNT162b2, CLL diagnosis and venetoclax/ibrutinib seem to be related with a lower humoral or T-mediated response. Nevertheless, the efficacy of mRNA vaccine in HM pts and the importance to continue the vaccine program even in non-responders after the first dose are supported in our study by demonstrating that a humoral and T-cell-mediated seroconversion should be observed even in the subsets of heavily immunocompromised pts.

Immunological Aspects of Richter Syndrome: From Immune Dysfunction to Immunotherapy

Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in patients with a previous or simultaneous diagnosis of chronic lymphocytic leukemia (CLL). Two pathological variants of RS are recognized: diffuse large B-cell lymphoma (DLBCL)-type and Hodgkin lymphoma (HL)-type RS. Different molecular mechanisms may explain the pathogenesis of DLBCL-type RS, including genetic lesions, modifications of immune regulators, and B cell receptor (BCR) pathway hyperactivation. Limited data are available for HL-type RS, and its development has been reported to be similar to de novo HL. In this review, we focus on the immune-related pathogenesis and immune system dysfunction of RS, which are linked to BCR over-reactivity, altered function of the immune system due to the underlying CLL, and specific features of the RS tumor microenvironment. The standard of care of this disease consists in chemoimmunotherapy, eventually followed by stem cell transplantation, but limited possibilities are offered to chemo-resistant patients, who represent the majority of RS cases. In order to address this unmet clinical need, several immunotherapeutic approaches have been developed, namely T cell engagement obtained with bispecific antibodies, PD-1/PD-L1 immune checkpoint blockade by the use of monoclonal antibodies, selective drug delivery with antibody-drug conjugates, and targeting malignant cells with anti-CD19 chimeric antigen receptor-T cells.

INTEGRATED BIOINFORMATIC ANALYSIS TO EVALUATE TARGET GENES AND PATHWAYS IN CHRONIC LYMPHOCYTIC LEUKEMIA

Objective: The most common type of leukemia, chronic lymphocytic leukemia (CLL), is characterized by progressive accumulation of monoclonal B cells with a specific immunophenotype in the blood, bone marrow, and lymphoid organ. The goal of this research was to use bioinformatic analysis to comprehend the molecular mechanisms causing CLL and to investigate potential targets for the diagnosis and therapy of CLL.&#x0D; Material and Method: Expression data from CLL patients with accession numbers GSE22529 and GSE26725 were downloaded from the GEO database for bioinformatic analysis. GSE22529 data was studied with samples from 41 CLL patients and 11 healthy groups, while GSE26725 data was studied with blood samples from 12 CLL patients and 5 healthy groups. GEO2R was used to find differentially expressed genes (DEGs) in CLL patient samples and healthy control samples. The DAVID program was used to perform GO and KEGG enrichment analyses on DEGs. Using the Cytoscape software, a protein-protein interaction (PPI) network was created, and hub genes associated with CLL were identified.&#x0D; Result and Discussion: DEGs with p 0.05 and log2FC 0, log2FC&gt;0 were chosen after analysis with GEO2R. In the GSE22529 dataset, 942 genes had higher expression levels in CLL patients compared with controls, while the expression of 1007 genes decreased. In the GSE26725 dataset, CLL patients had lower expression levels for 916 genes compared with controls, while 939 genes showed an increase in expression. 229 DEGs with higher expression levels and 308 DEGs with lower expression levels were found in both sets of data. It has been observed that these common genes, whose expression has changed, are enriched in protein processing in the ER, Chemokine, B-cell receptor, T-cell receptor, protein export pathways. Additionally, DDOST, RPL18, RPL18A, RPL19, RPL31, GNB3, GNB4, GNG11, GNGT1, NEDD8, UBE2M RBX1, FBXO21, SKP1, KLHL9 and CAND1 were identified as the most important genes. Our study's findings demonstrated that newly discovered genes and pathways may be candidates for CLL biomarkers that can be used for both the diagnosis and drug treatment of the disease.