Complication Of Chronic Lymphocytic Leukemia Research Articles

Pregnancy in Patents with CLL Systematic Review

Introduction: Chronic Lymphocytic Leukemia (CLL) is a hematologic malignancy characterized by the clonal expansion of non-functional, mature-appearing lymphocytes in the bone marrow, peripheral blood, and lymphoid tissues. While cases of CLL during pregnancy are rare,it is associated with many complications. It was reported that women with CLL are more susceptible to infections due to a weakened immune system; possibly leading to more complications. There is also increased risk of thrombocytopenia, which can increase the risk of bleeding during pregnancy and childbirth. This review aimed at identifying literature available on the complications in CLL and pregnancy as well as the data available on the potential therapeutic strategies. Methods: A scoping review of case reports that discuss pregnant patients who were diagnosed with CLL were isolated. The effects of the disease on pregnancy outcomes regarding both mother and fetus were identified. Animal studies, reviews or non-original articles, and non-English articles were excluded from our study. FDA labels of medications in CLL were reviewed for data on pregnancy and animal outcomes. Information on those medications in pregnant patients were also identified where available. Results: The search strategy across four databases yielded 448 articles. After eligibility assessment, 14 articles were included in the review. Cases were subdivided according to timing of pregnancy relative to CLL diagnosis (diagnosed before pregnancy or during pregnancy at early or late gestational periods). The pre-pregnancy reports were further subclassified based on the presence or absence of infection during pregnancy. None of the cases reported required immediate initiation of CLL therapy and only one case reported mortality post-delivery. This occurred in a patient with Richter transformation and no prior CLL treatments. There were no reported fetal malformations or severe adverse outcomes related to the infants in any of the reported pregnancies ( Figure 2). The included studies provided insights into various aspects of CLL during pregnancy, including patient demographics, diagnosis timing and methods, acquired infections, changes in white blood cell count, treatment approaches, pregnancy outcomes, and complications for both mother and fetus. From the marketed pharmacological alternatives for CLL, most were not studied in pregnant humans with CLL ( Figure 1). However, venetoclax and rituximab have some data in pregnant patients with non-CLL indications. A case reported a pregnant refractory AML patient who received venetoclax with high dose cytarabine and mitoxantrone at 24 weeks of gestation. Bone marrow at 27 weeks showed complete remission and labor was induced at 28 weeks + 5 days after corticosteroid-induced lung maturation. The infant had hyperbilirubinemia, transient B-cell depletion and required ventilation. The baby recovered from all complications, although possible long-term effects are still unclear. The mother underwent allogeneic hematopoietic stem cell transplant. In a 30-year-old female (pregnant at 28 weeks) with primary CNS lymphoma, weekly rituximab was given for 4 weeks with dexamethasone. After delivery through C-section at 31 weeks, the patient started definitive treatment with chemotherapy and autologous transplant. The infant required brief mechanical ventilation and had transient B-cell depletion at delivery until 4 months post-delivery. The baby required a course of post-exposure acyclovir despite not developing an infection. Both mother and baby survived with good outcomes at last follow-up (4 years post-delivery) Conclusion: Despite the rarity of CLL occurrence during pregnancy, there is evident need of further studies and management guidelines in this population. This review provides insights into the possible pregnancy-related concerns in women with CLL at different disease stages. While watchful waiting is generally recommended due to CLL's slow progression, individual evaluation is crucial. If treatment is necessary, delaying therapy until the second or third trimesters may help mitigate the risk of fetal malformations. The increased susceptibility to infections resulting from the combined immunosuppressive effects of CLL and pregnancy should be carefully considered

Risks and outcomes of hospitalizations in patients with chronic lymphocytic leukemia admitted with immune thrombocytopenia: an analysis of the National Inpatient Sample Database.

Immune thrombocytopenia (ITP) is a known autoimmune complication of chronic lymphocytic leukemia (CLL). Currently, there is limited data regarding the risk CLL confers on hospitalization outcomes in patients admitted with ITP.The National Inpatient Sample (NIS) database was queried using the International Classification of Diseases (ICD) codes to identify hospitalizations for ITP and then subclassified the data into hospitalizations with and without CLL. A multivariate logistic regression was designed to account for patient characteristics and comorbidities. The primary outcome was all-cause mortality. Secondary outcomes included major bleeding, gastrointestinal bleeding, intracranial bleeding, and the need for platelet transfusions, intravenous immunoglobulin, and splenectomy. Among 662,171 cases of ITP between 2005 and 2019, 15,672 had concurrent CLL. CLL patients were significantly older and had more comorbidities compared to patients without CLL. Multivariate analysis revealed CLL patients with ITP had a risk of all-cause mortality (odds ratio: 1.28, 95% CI: 1.19-1.37; p < 0.01). CLL patients also had a higher risk of complications, second-line ITP treatments, blood transfusions, and bleeding, with the exception of intracranial hemorrhage. Our study suggests CLL is an independent risk factor for increased morbidity and mortality among hospitalized patients with ITP. Prospective studies are needed to determine if refractoriness to conventional treatments for ITP can account these results.

Acalabrutinib and steroid for autoimmune thrombocytopenia due to relapsed chronic lymphocytic leukemia with severe bone marrow infiltration.

Thrombocytopenia is a frequent complication in chronic lymphocytic leukemia (CLL). Differentiating autoimmune thrombocytopenia from thrombocytopenia due to bone marrow infiltration is necessary for appropriate treatment, but sometimes difficult. Here we report a 60-year-old male patient with CLL who had achieved complete response after treatment with fludarabine, cyclophosphamide, and rituximab two years prior to presentation. He was admitted with severe thrombocytopenia that was unresponsive to intravenous immunoglobulin. Imaging studies revealed systemic enlarged lymph nodes and bone marrow aspiration was hypercellular with > 95% lymphocytes and scant megakaryocytes. Acalabrutinib 200 mg/day was administered for the treatment of CLL exacerbation. A gradual decrease in CLL cells and recovery of megakaryocytes in bone marrow were observed, but platelet counts remained low. Systemic administration of prednisolone 0.5 mg/kg, in addition to acalabrutinib, was started, considering the contribution of autoimmune thrombocytopenia; platelet recovery was rapid and sustained for more than a year. Even if bone marrow examination suggested thrombocytopenia due to direct leukemic infiltration, it is difficult to exclude the possibility of concomitant immunogenic thrombocytopenia. We conclude that for CLL patients with severe thrombocytopenia, repeating bone marrow examination and concurrent immunosuppressive therapies and treatment of the underlying CLL may be beneficial.

A Retrospective Study on the Efficacy of Subcutaneous Immunoglobulin as Compared to Intravenous Formulation in Patients with Chronic Lymphocytic Leukemia and Secondary Antibody Deficiency.

Secondary antibody deficiency (SAD) is a common complication in chronic lymphocytic leukemia (CLL) which favors the development of life-threatening infections. Subcutaneous immunoglobulins (IG) (SCIG) have been proven to be as effective as intravenous immunoglobulin (IVIG) in primary immunodeficiencies. Since only a few studies investigated SCIG in secondary antibody deficiency, the aim of this study was to assess the efficacy and safety of SCIG or IVIG in CLL patients with secondary antibody deficiency. One hundred and sixteen CLL patients were recruited, 63% were males, and the median age was 68 years; 44% had bronchiectasis and 76% never smoked. Forty-nine patients received IVIG and 88 SCIG, including 28 patients who shifted from IVIG to SCIG. Despite similar baseline IgG levels, patients receiving SCIG achieved higher IgG after at least +6 months (p = 0.0009). We observed that SCIG can decrease the cumulative incidence of first (HR 0.39 p < 0.0001) and second (HR 0.56 p = 0.0411) infection more than IVIG. The effect was remarkable in that patients were able to reach at least 6 g/L of IgG after 6 months of treatments (p < 0.0001). Replacement therapies were well tolerated with less adverse events and a lower discontinuation rate in patients was managed with SCIG than IVIG. In this study we describe the clinical features of a large cohort of CLL with secondary antibody deficiency receiving IG. We demonstrated that SCIG are active and well tolerated drugs that allows to reach higher IgG levels and decrease the rate of infections better than IVIG, in particular when IgG levels reach 6 g/L.

The Use of Novel Therapies Reduces the Risk of Autoimmune Complications in CLL: A Population-Based Study in British Columbia

Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are known autoimmune complications of chronic lymphocytic leukemia (CLL). Current literature has established that autoimmune cytopenias (AICs) secondary to CLL can arise prior to or in reaction to a therapy, such as Fludarabine, and therefore it is important to assess the roles novel therapies play with respect to autoimmune cytopenias. In this study we assessed the presenting characteristics and outcomes of patients (pts) with CLL who developed AICs. An electronic database search of 1056 patients with confirmed diagnosis of CLL who presented at St Paul's Hospital, Vancouver, Canada over 30 years and between 1991 and 2021 was performed with 520 having a complete data set. 276 pts (53%) who have undergone at least one treatment for their confirmed CLL presented with a full dataset. Of the 276 pts, 28 (10.1%) developed an autoimmune cytopenia secondary to CLL, with 20 pts developing AIHA, 5 pts developing ITP, and 3 pts developing both AIHA and ITP throughout the course of their treatments. Patients' characteristics are as detailed in the table. Time taken to develop an AIC (AIC Progression Free Survival) was then calculated using IBM SPSS and then incorporated into the Kaplan Meier method. Patients who had taken a novel therapy (Ibrutinib, Acalabrutinib, Venetoclax) at any point prior to developing an AIC were defined as the novel-therapy group. Patients who had not received any novel therapy prior to developing an AIC were defined as the non novel therapy group. At 50 months, 11 pts in the non novel therapy group (4.9%) developed an AIC, while 0 of the pts (0%) in the novel therapy group developed an AIC. At 100 months, 16 pts in the non novel therapy group (7.1%) developed an AIC, while 0 of the pts in the novel therapy group developed an AIC (p=0.014). On bivariate analysis novel therapies maintained high significance as a preventative treatment, with the number of AIC diagnoses negatively correlating with the number of pts treated with novel therapies (p=0.011). Other possible predictive markers for AICs were evaluated through bivariate and multivariate analysis. On bivariate analysis, the development of AICs significantly correlated with an increase in the number of treatments the patient received due to increased disease progression (p=0.001). Multivariate analysis through cox regression shows that factors such as greater age at diagnosis, male gender, and the lack of treatment with novel therapies are significant predictors for development of AICs (P<0.05). This study has demonstrated the significant preventative effect novel therapies can have on AICs in CLL. Incorporating novel therapies as a first line treatment presents as a reasonable strategy in reducing risk of AICs for patients that present with the other risk factors such as greater age at diagnosis and male gender. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CLL-069 Diagnosis and Management of Infectious Complications in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is an actual issue of oncology due to the increase of morbidity, frequent and therapy-resistant relapses, the development of infectious complications, commonly leading to the unfavorable prognosis. The identification of diagnostic features and management outcomes of infectious complications in CLL. We realized the case-control study of 82 CLL patients, who were treated at the Institute of Oncology in Moldova between 2000-2021. The diagnosis was proved according to the IWCLL criteria based on the complete blood count with the detection of lymphocytosis ≥ 5×109/l, bone marrow aspiration with lymphocytic infiltration ≥30% and immunophenotyping. The study was related to the outpatient and hospitalized care. The study included CLL patients of 45-86 years old (median age 66.2 years). There were 47 men (57.3%) and 35 women (42.7%). According to the Binet Classification, 54 (65.9%) patients were placed in stage A and 28 (34.1%) in stage B. The overall survival (OS) estimated the long-term results. The study of the age structure revealed the predominance of patients of 60-79 years old. Twenty-two (40.8%) stage A patients experienced the CLL transformation into stage B. Transformation into stage C was observed in 10 (35.7%) patients. The respiratory bacterial infections turned out to be frequently diagnosed (29 patients, or 80.6%): acute pneumonia in 10 (27.8%), acute bronchitis in 7 (19.4%), relapse of chronic bronchitis in 11 (30.6%), and tuberculosis in 1 (2.8%) patient. Viral herpetic complications were diagnosed in 2 (5.6%) cases. Infectious complications of the other systems were detected in 5 (13.8%) patients: nephro-urinary infections in 3 (8.2%) and acute otitis in 2 (5.6%). Death occurred over a period of 3-19 years in 16 (19.5%) patients, due to infectious complications in 6 (37.5%), as a result of CLL progression in 5 (31.3%), due to the secondary tumors in 4 (25.0%), and acute cerebrovascular accident in 1 (6.2%). The 3- and 5-year OS was 100% and 95.7% in patients with stage A and 84.8% and 55.4% in stage B. Infectious complications are frequent manifestations and cause of death in CLL, especially in stage B.

INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA – CHALLENGING ISSUES OF HEMATO-ONCOLOGY

Theaim of the study was to identify the diagnosis features and origin of the infectious complications in chronic lymphocytic leukemia (CLL). Our observational study enrolled 82 patients (pts) with different CLL phases, who were managed at the Institute of Oncology of Moldova from 2000 to 2022. The pts age ranged between 45-86 years (median age 66.2 years). There were 47 (57.3%) males and 35 (42.7%) females. The diagnosis was proved by histopathological, immunohistochemical, cytological and immunophenotyping examinations. We used IWCLL criteria on a basis of lymphoid cells rate in the blood count and bone marrow aspirate. Accordingto Binet classification, stage A was revealed in 54 (65.9%) pts, stage B – in 28 (34.1%). Infectious complications developed in 36 (43.9%) cases. Respiratory bacterial infections were diagnosed in 29 (80.6%) pts, commonly comprised the relapses of chronic bronchitis - in 11 (30.6%) and acute pneumonia - in 10 (27.8%). Herpetic infection was diagnosed in 2 (5.6%) cases. Other infectious complications included nephro-urinary tract in 3 (8.2%) pts and acute otitis in 2 (5.6%). Fatal outcomes occurred in 16 (19.5%) pts, including 6 (37.5%) with infections, 5 (31.3%) with CLL progression. The infectious complications proved to be the common manifestations and causes of death in CLL, especially in stage B.

Richter Transformation in Chronic Lymphocytic Leukemia with Hypercalcemia and Acute Kidney Injury Presenting as Altered Mental Status: A Case Report

Introduction: Richter’s transformation is a deadly complication of chronic lymphocytic leukemia (CLL) associated with high mortality. This transformation involves the development of an aggressive, diffuse large B cell lymphoma in the setting of a chronic, underlying case of CLL. Although it is rare, Richter’s transformation is important to identify in patients with a history of CLL because of its significant mortality if left untreated. In the setting of CLL, there are many ways in which patients can present if they are currently undergoing a Richter’s transformation. Case Description: Patients may present with symptoms common to CLL which include but are not limited to fatigue, easy bruising, weight loss, etc., or they may present more unusually, as in the case that will be presented here: with altered mental status, fall, hypercalcemia and acute kidney injury (AKI). Discussion: With the current state of affairs due to COVID-19, it is also important to recognize the potential complications of patients with this disease state that are positive for COVID-19, leading to further complications such as disseminated intravascular coagulation (DIC). Recognizing these patients, and directing their care appropriately is important for their disease progression and outlook.

Outcomes of Richter’s syndrome in patients with chronic lymphocytic leukemia (CLL) treated with platinum or anthracycline based chemotherapy with or without a BTK inhibitor (BTKi).

e19511 Background: Richter’s syndrome (RS) is a rare complication of chronic lymphocytic leukemia (CLL) and the median survival is generally poor. Evidence is limited regarding the biology of the disease, treatment and outcomes. Methods: We retrospectively reviewed pts diagnosed (dx) with pathologically confirmed RS who presented at the University of Miami Sylvester Cancer Center between 2011 and 2020. Informed consent was provided through IRB-approved protocols. Descriptive statistics were utilized and overall survival (OS) was calculated from RS diagnosis to death or last follow-up by Kaplan-Meier. Results: 33 patients with RS, including 87.9% diffuse large B-cell lymphoma-type RS and 12.1% Hodgkin lymphoma-type RS were identified. Median time from CLL dx to RS transformation was 37months (m). Most patients presented with elevated LDH 75%, bulky lymphadenopathy 66%, and adverse genetic features, such as TP53 disruption 52% or complex karyotype 81%. FISH at RS dx: del(17p) 37%, del(11q) 17%, trisomy 12 58%. ORR to first line therapy was 75.8% (55% CR, 27% PR), but of those who achieved CR, 44% relapsed. Median PFS (mPFS) was 10m for the anthracycline-based chemotherapy group (ABC) with a CR of 50%, compared to 15.5 m for the platinum-based chemotherapy group (PBC) and a CR of 60%. Similar OS were observed regardless of the chemotherapy regimen with median OS (mOS) of 60 m in the ABC group vs 59.5 m in the PBC group. Notably, the addition of a BTKi to chemoimmunotherapy lead to a mOS of more than 10 years in BTKi-naïve pts compared to 5.1 years in BTKi-exposed pts and 1.8 years in pts who did not receive a BTKi for RS treatment. Conclusions: Patients who develop RS often have high risk CLL, especially complex cytogenetics. Although a large proportion of pts with RS respond to frontline therapy, almost half relapse. While mOS is similar for anthracycline and platinum-based chemotherapies, platinum-based chemotherapy can lead to superior CR and PFS. BTKi-naïve pts who receive a BTKi with chemotherapy for RS treatment have superior mOS.

Outcomes of Hodgkin variant Richter transformation in chronic lymphocytic leukaemia and small lymphocytic lymphoma in British Columbia.

Hodgkin variant Richter transformation (HvRT) is a rare and challenging complication of chronic lymphocytic leukaemia (CLL) for which information on prognostic factors and treatment approaches remain limited. We analysed characteristics and survival outcomes of a population-based cohort of 32 patients with HvRT identified in British Columbia over a 40-year period. Median interval from CLL diagnosis to HvRT was 5.6 years (range, 0-33.6), with five cases diagnosed concurrently. Most patients (80%) had treatment for CLL prior to HvRT. Median age at HvRT was 71 years (range, 51-86) and the majority of patients had high-risk disease, including stage 3-4 in 87% and International Prognostic Score (IPS) ≥ 4 in 65%. Two-year progression-free (PFS) and overall survival (OS) from HvRT were 47% (95% CI: 29%-64%) and 57% (95% CI: 38%-72%), respectively. OS from HvRT was significantly worse in those with anaemia (p= 0.02), elevated lactate dehydrogenase (p= 0.04), high IPS (p= 0.04), and worse performance status (p= 0.001). For those treated with curative-intent ABVD/ABVD-like therapy, 2-year PFS and OS were 70% (95% CI: 45%-85%) and 74% (95% CI: 49%-89%), respectively. In this real-world population-based cohort, HvRT was associated with poor clinical outcomes overall; however, those able to tolerate curative-intent therapy had similar survival to older patients with de novo HL.

ІМУННІ ЦИТОПЕНІЇ У ХВОРИХ НА ХРОНІЧНУ ЛІМФОЦИТАРНУ ЛЕЙКЕМІЮ (ОСОБЛИВОСТІ ПЕРЕБІГУ, ПРОГНОСТИЧНІ МАРКЕРИ)

Background: Immune cytopenia (IC) is one of the major complications in chronic lymphocytic leukemia (CLL). The paper describes the peculiarities of different immune cytopenia in CLL patients and the importance of individual prognostic markers in the course of the disease. Methods: We observed 62 patients with CLL complicated by immune cytopenia. Among these patients 30 had autoimmune hemolytic anemia (AIHA), 18 experienced immune thrombocytopenia (ITP), 10 had Fisher-Evans syndrome (FES), 3 were diagnosed with partial red cell aplasia (PRCA), and immune neutropenia (IN) was revealed in 1 patient. In addition to general examination and laboratory studies, the following examinations were performed: immunophenotyping of peripheral blood lymphocytes, flow cytometry (CD5; CD19; CD20; CD23; CD38; ZAP70), Coombs test, a molecular cytogenetic study of peripheral blood lymphocytes using the FISH method with TP53 and ATM probes, the level of ß2-microglobulin. Results: It was established that the overall survival of CLL patients with IC depends on the form of the latter. The median overall survival in patients with Fisher-Evans syndrome was the shortest (75 months), slightly better survival was observed in patients with AIHA (median 80 months), the best survival was found in patients with ITP (median not reached). Among unfavorable markers of CLL with IC, there is the presence of del 11q22.3. Unfavorable prognostic markers were also the following: a positive Coombs test, high levels of ZAP 70 expression, and high levels of ß2-microglobulin

Evidence of a Synergistic Cross-Talk between the B Cell Receptor (BCR) and Nicotinamide Phosphoribosyl Transferase (NAMPT) in Richter's Syndrome Patient-Derived Xenograft Models: Therapeutic Implications

Background: A rare complication of Chronic Lymphocytic Leukemia (CLL), Richter's Syndrome (RS) represents the transformation of a pre-existing CLL into a Diffuse Large B-cell Lymphoma (DLBCL), generally associated with poor prognosis. Current therapeutic approaches are limited and do not significantly reduce disease progression. For these reasons there is intense investigation to identify potentially druggable molecular circuits, opening the way to innovative combination therapies.Among the several oncogenic signalling pathways that may contribute to disease progression, the B Cell Receptor (BCR) is a main driver and an actionable target. We previously showed that BCR ligation in CLL cells increases expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage NAD pathway starting from nicotinamide, a finding in line with the notion of oncogenic-driven metabolic reprogramming. In this context, increased NAMPT expression leading to heightened NAD+ levels could sustain proliferation through the modulation of the activity of several intracellular enzymes, including sirtuins (NAD-dependent deacetylases).Aim: This work explores the connections between BCR signalling and the NAMPT/NAD/sirtuin axis in RS cells, asking the question of whether BCR and NAMPT can be simultaneously targeted.Methods: RS-PDX cells were freshly purified from tumor masses grown in mice and immediately used for short ex-vivo experiments. For in vivo experiments, NSG mice were injected subcutaneously with RS-PDX cells, which were left to engraft until a palpable mass was evident. Mice were then randomized to receive duvelisib, OT82 or a combination of the two for two consecutive weeks. Control mice were similarly treated with vehicle only. Mice were under a niacin-free diet.Results: By using our 4 RS patient-derived xenografts (PDX) models, we invariably observed high levels of NAMPT expression. High levels of NAMPT expression were also observed in 15 primary RS lymph node biopsies analyzed by RNA sequencing. BCR engagement through αIgM polyclonal antibodies significantly up-regulated NAMPT expression, as determined by qRT-PCR and protein analysis, with a concomitant increase in intracellular NAD+ levels. We then asked whether RS cells are sensitive to NAMPT inhibition, alone or in combination with drugs that target the BCR pathway. As most RS patients would likely have been treated during the preceding CLL phase with a BTK inhibitor, possibly developing resistance, we turned to PI3K inhibitors, which are less commonly used for CLL therapy. As NAMPT inhibitors (NAMPTi) we used both FK866 and OT-82, which are validated small molecules. Results indicated that the combination of the dual PI3K-δ/γ inhibitor duvelisib, with either FK866 or OT-82 induces dramatic apoptosis in all 4 models tested, as confirmed by annexinV/PI staining, by caspase 3 activation and by a significant drop in ATP and NAD+ levels. Importantly, two RS-PDX models (RS9737 and RS1316) were fully resistant to NAMPTi used alone, likely due to high levels of nicotinate phosphoribosyltransferase (NAPRT), which is the rate-limiting enzyme in the NAD salvage pathway that starts from nicotinic acid. However, addition of duvelisib, which was mildly effective when used alone, was followed by marked apoptosis even in these two models.Molecular dissection of the pathway showed that the combination of duvelisib and NAMPTi was followed by complete inhibition of the PI3K pathway, which was only partially blocked by duvelisib alone, even at high doses. The connection between NAMPT and PI3K is represented by cytoplasmic sirtuins, particularly SIRT2, which activate AKT through de-acetylation. Immunoprecipitation and two-dimensional gel electrophoresis showed that in the presence of NAMPTi, the amount of acetylated, i.e., inactive, AKT increased considerably. Consistently, treatment of RS-PDX mice with a combination of duvelisib and OT-82 was followed by significantly higher responses and longer animal survival.Conclusions: These results highlight a crosstalk between BCR signalling and NAMPT/sirtuin axis in RS models, showing the increased efficacy of the dual targeting (i.e., PI3K-δ/γ and NAMPT), and supporting this novel and promising therapeutic strategy for the treatment of RS patients. DisclosuresDeaglio: Heidelberg Pharma: Research Funding; Astra Zeneca: Research Funding.

Efficacy of Ibrutinib Monotherapy in Pre-Clinical Mouse Models of Richter Transformation: Ibrutinib Effectively Reduces the Incidence of Richter Transformation but Fails in Treating Transformed Lymphoma, Especially in Primary Lymphoid Tissue

Richter's transformation (RT) is a complication of chronic lymphocytic leukemia (CLL) characterized by the development of an aggressive lymphoma, typically diffuse large B cell lymphoma (DLBCL). RT is associated with high expression of activation-induced cytidine deaminase (AID) and aberrant somatic hypermutation of non-immunoglobulin genes. Current frontline therapy of CLL, ibrutinib, eliminates AID + CLL cells and alters tissue microenvironment to Th1-biased niches; however approximately 10-20% of CLL patients develop RT upon ibrutinib treatment. In addition, ibrutinib leads to a clinical response in only ~40% of RT patients. Thus, RT remains an important unmet challenge for CLL patients and the mechanism of RT development during ibrutinib treatment is poorly understood.To determine the contributions of AID and T cells in RT development, and to understand the efficacy of ibrutinib in the treatment of RT, we first created patient-derived xenografts (PDXs) with samples from three RT patients who were refractory to (immuno)chemotherapy but had not previously received ibrutinib. In each case, the B-lymphocytes were larger in size and expressed lower levels of CD5 but higher levels of activation markers compared with the CLL cell counterpart. In PDXs, ibrutinib treatment led to significantly less RT cells in spleen with percentage of inhibition ranging from 28-60% for all three cases. Notably, AID levels were similar in RT cells residing in spleen of ibrutinib-treated and control mice. The numbers of T cells were also similar, although Th1:Th2 ratios were significantly increased by ibrutinib (control vs ibrutinib group: 33% vs 42%, P=0.01). Interestingly, the growth and survival of RT cells located in bone marrow (BM) were not affected by ibrutinib.We then investigated the efficacy of ibrutinib in the prevention and treatment of RT in a novel strain of TCL-1 mice, TCL1/Igκ-AID mice, that have AID overexpressed solely in B lymphocytes. These mice develop accelerated CLL disease, have shorter overall survival (OS), and bear increased numbers of AID signature mutations in genes that are drivers in CLL and DLBCL.First we injected primary splenocytes from a TCL1/Igκ-AID mouse (A-31) into wild-type C57BL/6 mice. A week later, mice were treated with vehicle or ibrutinib continuously for 3 weeks (N=5 per group, duplicated experiments). At the end of treatment, RT cells were found in 25% of recipients in the control group and only in 10% of ibrutinib-treated recipients. Ibrutinib-treated animals had overall smaller spleens and lymph nodes (LNs) filled with significantly less CLL or RT cells. Importantly, the balance of Th1/Th2 cytokines was also significantly changed by ibrutinib (Th1/Th2 in control vs ibrutinib: 25% vs 47%, P=0.01). However, again RT cells in BMs of treated and control animals were similar.We then repeated the experiment to determine overall survival by giving the mice vehicle or ibrutinib continuously. Compared to the TCL1/Igκ-AID (A-31) donors, recipients treated with control vehicle developed more aggressive CLL with shorter OS. However, Ibrutinib did not change the OS; both control and ibrutinib treated recipients had similar OS with all the mice developed and died from RT eventually.Finally, to determine the efficacy of ibrutinib in the treatment of RT in TCL1/Igκ-AID mice, we sorted A-31-derived RT cells collected from LNs, and injected these into C57BL/6 mice. Mice then received treatment for 3 weeks. Notably, ibrutinib did not change the numbers or sizes of LNs or spleens. The numbers of RT cells at all sites, including BM, remained the same. In both groups, the number of T cells and the Th1:Th2 were not altered by ibrutinib.In summary, our data suggest that ibrutinib is somewhat effective against primary RT cells in the spleen in PDX models but not at all in the aggressive TCL1/IgK-AID mouse model. This might be because ibrutinib does not reduce AID levels in tissue-resident RT cells. Notably, although RT cells in spleens and LNs respond to ibrutinib, those residing in BM are resistant in both PDX and TCL1/IgK-AID models. This suggests different clones or different ibrutinib-responsiveness of RT cells in primary versus secondary lymphoid tissues. Overall, these results suggest that ibrutinib does not prevent or cure RT. Additionally, TCL1/Igκ-AID mice might provide a model to study the development, prevention, and treatment of RT without the influence of prior chemo- or other therapies. DisclosuresWirtz: Abbvie: Current Employment. Szafer-Glusman: AbbVie: Current Employment, Other: Stock or other ownership.

Leukostasis aggravated by red blood cell transfusion in a chronic lymphocytic leukemia patient

Abstract Introduction/Objective Leukostasis/symptomatic hyperleukocytosis is commonly seen in acute leukemias and is characterized by high blast counts and symptoms of decreased tissue perfusion with a one-week mortality of 20-40%, if left untreated. It is a rare complication in chronic lymphocytic leukemia (CLL) and is seen in CLL patients with white blood cell (WBC) counts &amp;gt; 500x10^9/L. Studies have shown that transfusion of blood products prior to decreasing the WBC count may lead to increased blood viscosity and worsen leukostasis. We report a CLL patient with a lower WBC count presenting with symptoms of leukostasis, further worsened by a red blood cell (RBC) transfusion prior to leukapheresis. Methods/Case Report A 73-year-old male with history of CLL for 5 years, hypertension and chronic kidney disease presented with acute dyspnea for 1 day. The WBC count was 208x10^9/L, hemoglobin was 6.5 g/dL, troponin I was 1.554 ng/mL, creatinine was 1.68 mg/dL and chest x-ray showed bilateral interstitial lung edema. The patient was diagnosed with acute hypoxic respiratory failure, acute kidney injury and myocardial infarction due to leukostasis. He received RBC transfusion, shortly after which his dyspnea worsened. There were no other signs or symptoms that could suggest a transfusion reaction. A single leukapheresis was performed following which there was a significant improvement in symptoms with a drop in WBC count to 123.1x10^9/L and creatinine to 1.3 mg/dL. Results (if a Case Study enter NA) NA Conclusion CLL may present with symptomatic hyperleukocytosis at lower leukocyte counts than has been described in the literature. Symptoms due to leukostasis can be precipitated/worsened by transfusion of blood products due to increased blood viscosity. It is critical to identify the signs and symptoms of this medical emergency as prompt diagnosis and management with leukapheresis significantly reduces the leukocyte count and blood products should be transfused slowly during or after leukapheresis.

Richter Transformation in Chronic Lymphocytic Leukemia: Update in the Era of Novel Agents.

Simple SummaryRichter transformation is a significant and devastating complication of chronic lymphocytic leukemia. While its pathogenesis has been well-studied in terms of genetic and molecular changes and its diagnosis has been made easier by imaging and pathological techniques, its treatment is still an issue. Most patients are resistant to chemo-immunotherapy, and even novel agents do not seem to improve the prognosis in a significant way. Therefore, new combinations and novel drugs are currently being tested. In the current review, we summarize new data about the pathophysiology, biological, and clinical basis of Richter transformation, as well as the different treatments of this condition.Richter transformation (RT) is a poorly understood complication of chronic lymphocytic leukemia (CLL) with a dismal prognosis. It is associated with a switch in histopathology and biology, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or less frequently to Hodgkin’s variant of Richter transformation (HVRT). It occurs in 2–10% of CLL patients, with an incidence rate of 0.5–1% per year, and may develop in treatment-naïve patients, although it is more common following therapy. In recent years, there has been a deeper understanding of the molecular pathogenesis of RT that involves the inactivation of the TP53 tumor suppressor gene in 50–60% of cases and the activation of aberrations of NOTCH1 and MYC pathways in about 30% of cases. Compared to the preceding CLL, 80% of cases with DLBCL-RT and 30% of HVRT harbor the same IGHV-D-J rearrangements, indicating a clonal evolution of the disease, while the remaining cases represent de novo lymphomas that are clonally unrelated. Despite advances in understanding the molecular variations and the pathogenesis of the disease, there is still no significant improvement in patient outcomes. However, if no clinical trials were designed for patients with RT in the past, now there many studies for these patients that incorporate new drugs and novel combinations that are being explored. In this review, we summarize the new information accumulated on RT with special emphasis on results involving the novel therapy tested for this entity, which represents an unmet clinical need.

Vaccination in Patients with Chronic Lymphocytic Leukemia: Current Problems

Relevance. Infections are the most common complication of chronic lymphocytic leukemia (CLL). According to registry studies, infections are the cause of death in 10–20% of patients. The emergence of new therapies for CLL has led to a decrease in mortality due to CLL progression, while mortality from infections has remained constant in recent decades.The aim of this literature review is to analyze the effectiveness of vaccine prophylaxis in patients with CLL as well as predictors of vaccine inefficiency according to published data, to explore current guidelines.Conclusions. The mechanisms of immune dysfunction in CLL are complex and associated with both the disease itself and the therapy. Numerous studies have shown that patients with CLL have an inadequate response to most vaccines given routinely in the general population. Vaccination in CLL patients remains a poorly developed topic. Additional clinical trials are needed to improve the effectiveness of vaccination in patients with CLL.

Specific features of T- and NK-cellular immunity in chronic lymphocytic leukemia.

Profound immunological dysfunction is the key factor determining the development of infectious complications in chronic lymphocytic leukemia (CLL). The aim of this work is to assess the features of the subpopulation composition of T-lymphocytes (T-helpers (Th), cytotoxic T-lymphocytes (Tcyt), T regulatory cells (Treg), T-NK cells, naive Th, Th-memory, activated T-lymphocytes, TCRγδ cells) and NK cells in peripheral blood of patients with newly diagnosed chronic lymphocytic leukemia (CLL) and receiving ibrutinib therapy. Hematological and immunophenotypic studies have been performed in 30 patients with previously untreated CLL, 122 patients on ibrutinib therapy and 20 healthy donors. The subpopulation composition of T-lymphocytes (Th, Tcyt, Treg, T-NK, naive T-helpers, memory T-helpers, TCRγδ cells, activated T-lymphocytes) and NK cells has been assessed on flow cytometer (FACSCanto II (BD)) using the following panel of monoclonal antibodies: CD45, CD19, CD3, CD4, CD5, CD8, TCRγδ, CD127, CD16, CD56, CD57 CD45RA, CD45R0, HLA-DR, CD25. Compared to controls all CLL samples were found to have higher the absolute number of T-lymphocytes, NK cells and their subpopulations, T-helpers (especially of memory T-cells), cytotoxic T-cells, regulatory T-cells, TCRγδ T-cells, activated T-lymphocytes, increased cytotoxic potential of NK cells in previously untreated CLL patients. Patients who received ibrutinib therapy have registered a positive trend towards recovery of the subpopulation composition of T-lymphocytes and NK-cells. CLL patients have been found to have quantitative and functional changes in the subpopulations of T-lymphocytes and NK cells, indicating dysregulation of the immune response, and a high risk of developing infections. Monitoring of immunological parameters for ibrutinib therapy make possible to estimate impact of ibrutinib on the adaptive anti-CLL immune response.

The Role of Novel Agents in Treating CLL-Associated Autoimmune Hemolytic Anemia.

Autoimmune cytopenias (AICs) have been reported as a common complication in chronic lymphocytic leukemia (CLL) with autoimmune hemolytic anemia (AIHA), accounting for most cases. According to iwCLL guidelines, AICs poorly responsive to corticosteroids are considered indication for CLL-directed treatment. Chemo-immunotherapy has classically been employed, with variable results, and little data are available on novel agents, the current backbone of CLL therapy. The use of idelalisib in the setting of AICs is controversial and recent recommendations suggest avoiding idelalisib in this setting. Ibrutinib, through ITK-driven Th1 polarization of cell-mediated immune response, is known to produce an immunological rebalancing in CLL, which stands as a fascinating rationale for its use to treat autoimmunity. Although treatment-emergent AIHA has rarely been reported, ibrutinib has shown rapid and durable responses when used to treat AIHA arising in CLL. There is poor evidence regarding the role of BCL-2 inhibitors in CLL-associated AICs and the use of venetoclax in such cases is debated. Furthermore, their frequent use in combination with anti-CD20 agents might represent a confounding factor in evaluating their efficacy. In conclusions, because of their ability to mitigate an immunological dysregulation that is (at least partly) responsible for autoimmunity in CLL, to date BTK-inhibitors stand out as the most suitable choice when treatment of autoimmune cytopenias is required.

Central Nervous System Involvement is Associated with Ibrutinib-Induced Severe Hyperleukocytosis and Controlled by the Combination of Intrathecal Chemotherapy in Chronic Lymphocytic Leukemia: A Case Report

Central nervous system involvement (CNSi) is a rare complication of chronic lymphocytic leukemia (CLL) with a very poor prognosis. Its diagnosis, predictive factors, and standard treatment remain elusive. Ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase, has been approved to treat CLL, yet little is known of its effect on the occurrence and management of CNSi. Here, we report, for the first time, an elderly CLL patient with secondary CNSi following ibrutinib-induced severe hyperleukocytosis, characterized by subcutaneous lesions and unmutated IgHV gene. Ibrutinib combined with intrathecal chemotherapy induced a prompt and durable remission of CNSi. This case indicates that severe hyperleukocytosis caused by ibrutinib is associated with the emergence of CNSi, and a combined treatment with intrathecal chemotherapy is effective and safe in the treatment of CLL patient with CNSi.

Can Treatment with Venetoclax for Chronic Lymphocytic Leukemia (CLL) Result In Autoimmune Hemolytic Anemia?

Patient: Female, 62-year-oldFinal Diagnosis: Autoimmune hemolytic anemiaSymptoms: AnemiaMedication:—Clinical Procedure: —Specialty: HematologyObjective:Unusual clinical courseBackground:Chronic lymphocytic leukemia (CLL) is a hematological disease characterized by the clonal proliferation and accumulation of neoplastic B lymphocytes in the blood, bone marrow, lymph nodes, and spleen. Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic anemia in which the destruction of erythrocytes is helped by anti-erythrocyte auto-antibodies. This has a controversial effect on the clinical outcome and survival of patients with CLL. Venetoclax, a second-generation BH3 mimetic compound, is one of the new therapies that has been approved for the treatment of CLL. Venetoclax disrupts the antiapoptotic signaling through BCL2. Common adverse events associated with venetoclax include neutropenia, thrombocytopenia, and diarrhea. This case report describes a patient with CLL who developed AIHA when treated with venetoclax.Case Report:A patient of 62-year-old woman, who was treated with multiple lines of therapy, presented autoimmune hemolytic anemia after treatment with venetoclax. The anemia was resolved after holding venetoclax and being treated with rituximab. In January 2019, there were reports of 7 patients developing AIHA related to veneto-clax therapy in Europe, according to the EudraVigilance database. How venetoclax can cause AIHA is not completely clear. This complication can happen when the erythrocyte antigen is altered by the drug that can produce antibodies. The other described mechanism is the binding of the drug with erythrocytes, which leads to production of an immune response.Conclusions:Although AIHA can be a complication of CLL, it may be caused by treatment with venetoclax. That may be confirmed after eliminating other causes.