scholarly journals ­Active AKT signaling triggers CLL towards Richter's transformation via over-activation of Notch1

Blood ◽  
2020 ◽  
Author(s):  
Vivien Kohlhaas ◽  
Stuart James Blakemore ◽  
Mona Al-Maarri ◽  
Nadine Nickel ◽  
Martin Pal ◽  
...  
Keyword(s):  
T Cells ◽  
S100 Protein ◽  
Significant Proportion ◽  
Lymphocytic Leukemia ◽  
Aggressive Lymphoma ◽  
Akt Phosphorylation ◽  
Recurrent Mutations ◽  
Genomic Aberrations ◽  
Richter’S Transformation ◽  
Richter's Transformation

Richter's transformation (RT) is an aggressive lymphoma which occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL-phase involving TP53, CDKN2A, MYC, and NOTCH1, however a significant proportion of RT cases lack CLL-phase associated events. Here, we report that high levels of AKT phosphorylation occurs both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in RT patients. Genetic over-activation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurrent mutations, we identified a profile of genomic aberrations intermediate between CLL and DLBCL. Multi-omics assessment by phosphoproteomic/proteomic and single-cell transcriptomic profiles of this Akt-induced murine RT revealed a S100-protein-defined subcluster of highly aggressive lymphoma cells, which developed from CLL cells, through activation of Notch via Notch ligand expressed by T cells. Constitutively active Notch1 similarly induced RT of murine CLL. We identify Akt activation as an initiator of CLL transformation towards aggressive lymphoma by inducing Notch signaling between RT cells and microenvironmental T cells.

a Rare Case of Chronic Lymphocytic Leukemia (CLL), Transforming to Two Different Types of Aggressive Lymphoma during the Course of the Disease.

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5650-5650
Author(s):  
Amir Azadi ◽  
Padmini Moffett ◽  
Mounika Mandadi ◽  
Goetz H Kloecker
Keyword(s):  
Lymph Node ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Rare Case ◽  
Cervical Lymphadenopathy ◽  
Lymphocytic Leukemia ◽  
Aggressive Lymphoma ◽  
Different Types ◽  
Richter’S Transformation ◽  
Richter's Transformation

Abstract A rare case of chronic lymphocytic leukemia (CLL), Transforming to two different types of aggressive lymphoma during the course of the disease. BACKGROUND Patients with chronic lymphocytic leukemia may have disease transformation to non-Hodgkin's lymphoma (DLBL)or prolymphocytic leukemia (PLL) To date there have been no cases in the english literatures reporting a CLL patient presenting with transformation to both of these different types of more aggressive diseases during the course of their disease. We describe a rare case of CLL who developed transformation to PLL and DLBL, also known as Richter's transformation(RT) respectively during the course of disease. CASE A 53 year old woman with no significant prior medical history who initially presented with leukocytosis of 14500 and cervical lymphadenopathy on physical examination. Excisional biopsy and microscopic examination confirmed the diagnosis of chronic lymphocytic leukemia with microscopic features of monotonous population of small mature-appearing lymphocytes. Immunohistochemical studies are positive for CD5 and CD23, CD38 and ZAP 70. Concurrent review of peripheral blood smear was showed leukocytosis with relative lymphocytosis and smudge cells. A computed tomography scan of the neck, chest, abdomen and pelvis performed and was remarkable for cervical lymphadenopathy and she was subsequently staged as RAI I of CLL/SLL. The patient was asymptomatic and was therefore observed expectantly for 10 months. Then due to progression of lymphocytosis and extensive cervical lymphadenopathy, she began treatment with chemotherapy consisting of Rituxan, Cytoxan and Fludarabine. After 18 months of being in remission after treatment she again developed cervical lymphadenopathy and night sweats. Exisional biopsy of left cervical lymph node performd and flow cytometric analysis of the lymph node was positive for CD-20, PAX-5, and BCL-2 . Also 97% of these B cells expressed CD38, which is associated with a more aggressive course in CLL, and was supportive for prolymphocytic transformation of CLL. She has been initiated on chemotherapy including bendamustine and Rituxan for a total of four cycles. Patient had a good response to treatment for nine months until she palpated a lymph node in left submandibular area and subsequent excisional lymh node biopsy showed recurrence of the disease with prolymphocytic transformation. The patient began to receive chemotherapy with (R-CHOP) regimen after confirmation of recurrence. A month after completion of chemotherapy, patient had developed increasing lymphadenopathy in neck. Microscopic exam of the biopsy showed foci of CLL/SLL cells and Some binucleated large cells with Immunohistochemical stains, positive for CD20 and weak positivity for CD5 and negativity for CD23, CD10 and BCL6. Immunohistochemical stain for KI-67 shows 70-80% proliferation rate in large cells and less than 10% proliferation rate in background CLL cells which indicates Richter's transformation of CLL/SLL to diffuse large B-cell lymphoma with an activated B-cell phenotype, which is the most common histologic variant of Richter transformation. CONCLUSION Chronic lymphocytic leukemia(CLL) is an indolent B-cell non-Hodgkin's lymphoma and is the most common leukemia in the western world with a heterogenous and mostly prolonged disease course, that may transform into higher grade lymphoma. Transformation of CLL to a more aggressive lymphoma occurs in about 5-10% of patients, and is generally accociated with acceleration of the disease and poor clinical prognosis. The transformation involves an increased number of Prolymphocytic cells, termed PLL transformation or the development of DLBCL which also reffered to as Richter's transformation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Chronic Lymphocytic Leukemia: A Rare Cause of Pathological Fracture of the Femur

2017 ◽  
Vol 5 (4) ◽  
pp. 232470961773513 ◽  
Author(s):  
Parita Soni ◽  
Nidhi Aggarwal ◽  
Anand Rai ◽  
Vivek Kumar ◽  
Kamholz Stephan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Endotracheal Intubation ◽  
Pathological Fracture ◽  
The United States ◽  
Left Knee ◽  
Lymphocytic Leukemia ◽  
Initial Presentation ◽  
Richter’S Transformation ◽  
Richter's Transformation

The incidence rate of chronic lymphocytic leukemia (CLL) in the United States is approximately 0.005%; men are at slightly higher risk than women. Bony involvement or pathological fracture rarely occurs in CLL, and it may be the initial presentation. An 85-year-old woman presented with acute respiratory failure secondary to pneumonia. Symptomatology included dyspnea. She was found to have pathological fracture of the femur caused by CLL. The diagnosis of CLL had been made 6 years previously, but the patient had refused therapy. On admission, the patient required endotracheal intubation, mechanical ventilation, and admission to the medical intensive care unit. Endotracheal intubation extubation was successful after 48 hours. The patient then complained of severe left knee pain. Bone radiograph and femoral computed tomography scan revealed acute pathological fracture of the left distal femur. There was no history of trauma. The fracture was stabilized with extension lock splint. Pathological fracture in patients with CLL is associated with hypercalcemia, Richter’s transformation, or multiple myeloma. This patient exemplifies the fact that pathological fracture can be caused by CLL in the absence of hypercalcemia, Richter’s transformation, or multiple myeloma and can be the initial presentation of CLL.

scholarly journals Recurrent Mutations within the Nfkbie gene: A Novel Mechanism for NF-κB Deregulation in Aggressive Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 297-297
Author(s):  
Larry Mansouri ◽  
Lesley-Ann Sutton ◽  
Viktor Ljungstrom ◽  
Sina Bondza ◽  
Linda Arngarden ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mutant Allele ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
B Cell Lymphomas ◽  
Tlr Signaling ◽  
B Cell Malignancies ◽  
Recurrent Mutations ◽  
Genomic Aberrations

Abstract Dysregulated NF-κB signaling appears to be particularly important in B-cell malignancies, with recurrent mutations identified within both the canonical and non-canonical NF-κB pathways, as well as in components of the B-cell receptor (BcR) and Toll-like receptor (TLR) signaling pathways. In chronic lymphocytic leukemia (CLL), although recurrent mutations have been identified in MYD88 (TLR signaling) and BIRC3 (non-canonical NF-κB pathway), their frequency is low (<3%) and hence the extent to which genetic aberrations may contribute to constitutional NF-κB activation remains largely unknown. To gain further insight into this issue, we designed a HaloPlex gene panel (Agilent Technologies) and performed targeted next-generation sequencing (NGS) (HiSeq 2000/Illumina) of 18 NF-κB genes in a discovery cohort of 124 CLL patients, intentionally biased towards poor-prognostic patients with either unmutated IGHV genes or high-risk genomic aberrations. Using a conservative cutoff of >10% for the mutant allele, we identified mutations (n=35) within 30/124 (24%) patients in 14/18 NF-κB genes analyzed. IκB genes, which encode for cytoplasmic inhibitor proteins, accounted for 20/35 (57%) mutations, with IκBε (encoded by NFKBIE) mutated in 8 patients; notably, 3/8 cases carried an identical 4bp deletion within exon 1 of NFKBIE. Prompted by these findings, we proceeded to validate our findings in an independent CLL cohort (n=168) using the same methodology as above and primarily focusing on cases with poor-prognostic features. We identified 30 mutations within 28 CLL patients in 11/18 NF-κB genes analyzed. Strikingly, 13/30 mutations were found within IκBε, with 10/13 patients carrying the same 4bp NFKBIE deletion. Notably, investigations into whether additional cases (within both the discovery and validation cohort) may harbor mutations of low clonal abundance (<10% mutant allele), led to the detection of the NFKBIE deletion in another 18 cases. Owing to the prevalence of this 4bp deletion within the NFKBIE gene, we developed a GeneScan assay and screened an additional 312 CLL cases. Collectively, 40/604 (6.6%) CLL patients were found to carry this frame-shift deletion within the NFKBIE gene, which is in line with a recent publication reporting that 10% of Binet stage B/C patients carried this mutation (Damm et al. Cancer Discovery 2014). Remarkably, the majority of these NFKBIE mutations (16/40) were found in a subgroup of patients that expressed highly similar or stereotyped BcRs and are known to have a particularly poor outcome, denoted as subset #1. This finding thus alludes to a subset-biased acquisition and/or selection of genomic aberrations, similar to what has been reported for subset #2 and SF3B1, perhaps as a result of particular modes of BcR/antigen interaction. We utilized proximity-ligation assays to test the functional impact of the NFKBIE deletion by investigating protein-protein interactions. This analysis revealed reduced interaction between the inhibitor IκBε and the transcription factor p65 in NFKBIE-deleted CLL cells; IκBε-knock-down shRNA experiments confirmed dysregulated apoptosis/NF-κB signaling. Finally, to assess whether the NFKBIE deletion could also be present in other B-cell malignancies, we screened 372 mature B-cell lymphoma cases using NGS or the GeneScan assay and found the deletion in 7/136 (5.1%) mantle cell lymphomas, 3/66 (4.5%) diffuse large B-cell lymphomas and 3/170 (1.8%) splenic marginal zone lymphomas. Taken together, our analysis revealed that inactivating mutations within the NFKBIE gene lead to NF-κB activation in CLL and potentially several other B-cell-derived malignancies. Considering the central role of BcR stimulation in the natural history of CLL, the functional loss of IκBε may significantly contribute to sustained CLL cell survival and shape the disease evolution. This novel data strongly indicates that components of the NF-κB signaling pathway may be prime targets for future targeted therapies not only in CLL but also other mature B-cell lymphomas. Disclosures No relevant conflicts of interest to declare.

Is Chronic Lymphocytic Leukemia Still Incurable?

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3929-3929
Author(s):  
Michael J. Keating ◽  
Constantine S Tam ◽  
William G. Wierda ◽  
Susan O'Brien ◽  
Deborah A. Thomas ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Cell Transplant ◽  
Second Malignancies ◽  
Mutation Status ◽  
Richter’S Transformation ◽  
Richter's Transformation

Abstract Abstract 3929 Introduction Up until now, Chronic Lymphocytic Leukemia (CLL) has been considered incurable except with an allogeneic stem cell transplant. In the last 10 years, evidence has demonstrated that chemo-immuotherapy with fludarabine, cyclophosphamide, and rituximab, (FCR) has significantly improved CR rates, overall survival (OS), and progression free survival 1. Long term follow up data for FCR at MDACC demonstrated that a significant proportion of patients (pts.) were free at 8 years2 raising the question of whether pts. are potentially cured. Definition of cure in a chronic disease such as CLL has not been addressed. To investigate this possibility we evaluated the outcome characteristics of 222 of the 300 patients (who commenced FCR more than 10 years ago) in our previously reported study of initial therapy with FCR in CLL2. Seventy eight (35%) pts were free of relapse and 127 (58%) were alive at 10 years (Fig. 1). Thirty three patients died in CR/PR of infection (5), second malignancies (8), Richter's transformation (8). MDS (9), and other causes (3). One hundred and sixty three pts. (73%) achieved CR, 22 pts. (10%) a nodular PR (nPR), 27 pts. (12%) a PR, and 10 (5%) failed treatment. The 10 year PFS correlates strongly with response, CR (41%), nPR+PR (15%) (Fig. 2). None of these patients were transplanted in remission. FISH analysis was not available at the time of this study. Conventional karyotyping demonstrated +12 (24 pts), del 11q (15), del 17p (4), other abnormalities (15), diploid (105), and in 59 patients the test was not done or had no metaphases. The worst outcomes were del 17p and del 11q each significantly inferior to diploid (+12) patients had the best time-to-treatment failure (TTF) with P<.09 compared to diploid. The 10-year TTF was significantly higher for Rai <3 versus 3 – 4 (P=.02), serum beta-2-microglobulin (β2M) value of ≤ 4 mg/L (p<.001), mutation status of IgVh (P<.001) and number of courses of FCR received. (Table 1) The causes for receiving <6 courses of FCR were persistent cytopenia (15), infections (6), resistance (5), Richter's transformation and other malignancies (9), autoimmune hemolysis (5), and other causes and lost to follow-up (16). Of the 77 patients who are still in remission at 10 years, two have relapsed and one developed Richter's transformation. Four of 21 patients checked had no residual disease in their blood at 10 years by 4-parameter flow cytometry. All other 10 yr. TTF patients are being contacted to provide blood for 4-parameter flow residual disease. Conclusion The present data suggest that one-third of patients treated with chemoimmunotherapy are potentially cured of CLL. The characteristics most strongly associated with 10 yr. TTF were Rai stage, serum β2M level, mutation status, and tolerance of chemotherapy. Second malignancies and transformations are emerging as significantly impairing the likelihood of cure. Disclosures: No relevant conflicts of interest to declare.

Characteristics and Prognosis of Patients with Aggressive Chronic Lymphocytic Leukemia and Richter's Transformation: Correlation Between FDG/PET, Histology and Clinical Outcomes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 927-927
Author(s):  
Lorenzo Falchi ◽  
Long Xuan Trinh ◽  
Edith M. Marom ◽  
Mylene Truong ◽  
Ellen Schlette ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Outcomes ◽  
Fdg Pet ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Bulky Disease ◽  
Standardized Uptake Values ◽  
Richter’S Transformation ◽  
Richter's Transformation

Abstract Abstract 927 Introduction. Richter's transformation (RT) occurs in 2–8% of pts with chronic lymphocytic leukemia (CLL) and is associated with poor prognosis. Moreover, pts with CLL often show clinical and/or histologic features of aggressive disease, but do not fulfill the histological criteria for RT. FDG/PET is a diagnostic tool in hematologic malignancies. Standardized uptake values (SUV) measured by FDG/PET correlates with tumor cell proliferation and aggressiveness. FDG/PET is increasingly used to evaluate pts suspicious for RT. We therefore reviewed the experience with FDG/PET in the diagnosis and management of pts with aggressive CLL and RT seen at our Institution and correlated FDG/PET data, histology, and clinical outcomes in these pts. Methods. We studied pts assessed with FDG/PET and concurrent lymph node biopsy (or marrow diagnosis of transformation). According to the histological characteristics pts were grouped in 3 categories: chronic phase (CP), increased aggressiveness (IA) or overt RT. IA was defined for this report by the presence of either increased number of large cells or ≥10% prolymphocytes in the tissue specimen. The extent of disease was assessed by FDG/PET and defined: limited = hypermetabolic sites with SUVbwmax≥5 on one side of the diaphragm; extensive = hypermetabolic sites with SUVbwmax≥5 on both sides of the diaphragm. After therapy, restaging FDG/PET was analyzed, when available, for response assessment. Results. 750 pts with CLL had at least 1 complete FDG/PET report, 422 were excluded from this analysis because of: no biopsy in 341 pts, no FDG/PET at time of biopsy in 34, concurrent cancer in 25, benign histology in 18, CP histology in pt with past RT/IA in 4. 328 pts had both FDG/PET and histological characterization and are the focus of this report. 93 pts had RT, 116 had IA and 119 had CP. Patient characteristics are summarized in table 1. We analyzed FDG/PET results in these 328 pts. Median highest SUV (SUVbwmax) was 17.9 (0-56.3) for pts with RT, 6.7 (0-37.8) for pts with IA and 3.6 (0-14.3) for pts with CP. Using an SUVbwmax cutoff of 5 sensitivity, specificity, positive and negative predictive value for the detection of RT were 88%, 48%, 40% and 91%, respectively. We next correlated FDG/PET result, histology and survival. Median overall survival (OS) was 7.9, 19.7, and 77.3 months in pts with RT, IA and CP, respectively. SUVbwmax correlated with OS. An SUVbwmax cutoff of 10 showed the highest discriminatory power: median OS was 56.4 months (95% CI: 36.4 – 71.3) in pts with SUVbwmax<10 vs 7.3 months (95% CI: 5.0 – 8.6) in pts with SUVbwmax≥10. OS of pts with RT or IA was similar for pts with SUVbwmax<10 (29.5 vs 21.4 months, p=.62) or ≥10 (7.6 vs. 5.9 months, p=.71). Sixty %, 38% and 13% of pts with RT, IA, and CP, respectively, had extensive disease. OS was not significantly different between pts with limited vs extended disease within pt groups with SUVbwmax<10 or ≥10 (p=.45 vs .06, respectively). Factors independently associated with inferior OS in multi variable analysis were: RT histology, age ≥65 ys, PS ≥2, bulky disease, prior therapy, and SUVbwmax≥10. All pts with RT or IA, and 71% of pts with CP received treatment. 95 pts had a FDG/PET performed as restaging. In these pts OS was not reached in pts with ≥66% reduction in SUVbwmax after therapy and 15.3 months in those without such reduction (p <.0001). Conclusion. In our experience, FDG/PET accurately suggested the presence of RT in pts with CLL. SUVbwmax correlates with OS in pts with transformed CLL, independently of disease histology and extension. Restaging FDG/PET also predicted OS in pts with RT or IA. Prospective studies to validate the role of FDG/PET in the evaluation and management of pts with CLL are ongoing Disclosures: No relevant conflicts of interest to declare.

scholarly journals Near-Tetraploidy Is Strongly Associated with Development of Richter's Transformation in Chronic Lymphocytic Leukemia Patients Receiving Ibrutinib

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3198-3198
Author(s):  
Cecelia R. Miller ◽  
Amy S. Ruppert ◽  
Nyla A. Heerema ◽  
Kami J. Maddocks ◽  
Jadwiga Labanowska ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Complex Karyotype ◽  
Advisory Committees ◽  
Data Set ◽  
Richter’S Transformation ◽  
Richter's Transformation

Abstract Ibrutinib is a promising targeted therapy for chronic lymphocytic leukemia (CLL). However, a small subset of patients progress on ibrutinib either through progressive CLL or Richter's transformation. Patients responding to ibrutinib and then progressing with Richter's transformation do so most commonly within the first 2 years of treatment and have an extremely poor prognosis. Identifying biomarkers associated with this transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas; however, its incidence in CLL has not been described. We investigated the prevalence of near-tetraploidy in CLL patients prior to starting ibrutinib and identified it as a pre-treatment biomarker for Richter's transformation. We examined near-tetraploidy in a large series of CLL patients enrolled across four ibrutinib clinical trials at the Ohio State University, for which extensive correlative studies and follow up data are available (previously described by Maddocks et al., JAMA Oncol, 2015). We identified this abnormality in 9 of 300 patients (3.0%, 95% CI: 1.4-5.6) in blood or bone marrow samples taken prior to starting therapy. Near-tetraploidy was detected by the presence of four signals with four or more fluorescence in situ hybridization (FISH) probes and confirmed in the metaphase karyotype of each patient in at least one cell. Near-tetraploidy was associated with aggressive disease characteristics including: Rai stage 3/4 (p=0.03), deletion 17p (p=0.03), and complex karyotype (p=0.01), as well as trisomy 12 (p=0.05). With a median follow-up time of 40.5 months, in patients positive with near-tetraploidy, one patient (11%) progressed with CLL on ibrutinib, six patients (67%) progressed with Richter's transformation, and two patients (22%) were still on treatment. Cumulative incidence of Richter's transformation was significantly higher in patients with near-tetraploidy (Figure; p<0.0001). Notably, near-tetraploidy was not associated with progression with CLL alone (p=0.53). In a multivariable model, both near-tetraploidy (HR 8.66, 95% CI 3.83-19.59, p<0.0001) and complex karyotype (HR 4.78, 95% CI 1.42-15.94, p=0.01) were independent risk factors for discontinuing ibrutinib due to Richter's transformation. Our results suggest that near-tetraploidy is a distinct biomarker to assess in patients initiating ibrutinib which would predict a high risk for Richter's transformation. As a biomarker it will be important to confirm this association in a second independent data set as well as interrogate the distinct pathophysiology of this genomic subset of CLL. Figure Figure. Disclosures Lozanski: Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding. Jones:Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Awan:Novartis Oncology: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Research Funding. Blum:Pharmacyclics: Research Funding. Woyach:Acerta: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding.

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