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Richter's Syndrome

Richter's Syndrome is a rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma; usually diffuse large B cell lymphoma (DLBCL). Under 10% of people with CLL develop Richter's syndrome (RS), usually several years after the original of diagnosis of CLL. There are at least two biologically different types of RS: most are clonally related where the CLL cells have transformed into DLBCL, whilst a small number are not clonally related, where the DLBCL cells are not directly related to the CLL.

Treatment of RS is covered in some of the resources listed on the page about Chronic Lymphocytic Leukemia

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Web Resources: Richter syndrome
Latest Research Publications

Web Resources: Richter syndrome (3 links)

Latest Research Publications

Arruga F, Bracciamà V, Vitale N, et al.
Bidirectional linkage between the B-cell receptor and NOTCH1 in chronic lymphocytic leukemia and in Richter's syndrome: therapeutic implications.
Leukemia. 2019; [PubMed] Related Publications
NOTCH1 mutations in chronic lymphocytic leukemia (CLL) lead to accumulation of NOTCH1 intracellular domain (NICD) and prolong signaling. These mutations associate with a more aggressive disease compared to wild-type (WT) CLL. In this work we demonstrate a bidirectional functional relationship between NOTCH1 and the B cell receptor (BCR) pathways. By using highly homogeneous cohorts of primary CLL cells, activation of NOTCH1 is shown to increase expression of surface IgM, as well as LYN, BTK, and BLNK, ultimately enhancing BCR signaling responses, including global mRNA translation. Upon BCR cross-linking, NOTCH1 itself is actively translated and increased on cell surface. Furthermore, BCR ligation induces calcium mobilization that can facilitate ligand-independent NOTCH1 activation. These data suggest that the two pathways are functionally linked, providing a rationale for dual inhibition strategies. Consistently, addition of the γ-secretase inhibitor DAPT to ibrutinib significantly potentiates its effects, both in vitro and in a short-term patient-derived xenograft model. While this observation may find limited applications in the CLL field, it is more relevant for Richter's Syndrome (RS) management, where very few successful therapeutic options exist. Treatment of RS-patient-derived xenografts (RS-PDX) with the combination of ibrutinib and DAPT decreases disease burden and increases overall survival.

Rogers TS, Gardner JA, Devitt KA
High-grade B-Cell lymphoma with
Autops Case Rep. 2019 Jul-Sep; 9(3):e2019090 [PubMed] Free Access to Full Article Related Publications
Richter transformation (RT), or Richter syndrome, is defined as the transformation of chronic lymphocytic leukemia (CLL) to an aggressive B-cell lymphoma. The vast majority, up to 99%, transform into diffuse large B-cell lymphoma (DLBCL), with a small subset (<1%) becoming classical Hodgkin lymphoma. Approximately half of RT cases progress through a pathway involving dysregulation of C-MYC. High-grade B-cell lymphoma (HGBL) is a recent diagnostic category of aggressive B-cell lymphomas set forth in the updated 2017 WHO Classification of Hematopoietic and Lymphoid Tissues. HGBL with

Reinert CP, Federmann B, Hofmann J, et al.
Computed tomography textural analysis for the differentiation of chronic lymphocytic leukemia and diffuse large B cell lymphoma of Richter syndrome.
Eur Radiol. 2019; [PubMed] Related Publications
OBJECTIVE: To test the hypothesis that both indolent and aggressive chronic lymphocytic leukemia (CLL) can be differentiated from diffuse large B cell lymphoma (DLBCL) of Richter syndrome (RS) by CT texture analysis (CTTA) of involved lymph nodes.
MATERIAL AND METHODS: We retrospectively included 52 patients with indolent CLL (26/52), aggressive CLL (8/52), and DLBCL of RS (18/52), who underwent standardized contrast-enhanced CT. In main lymphoma tissue, VOIs were generated from which CTTA features including first-, second-, and higher-order textural features were extracted. CTTA features were compared between the entire CLL group, the indolent CLL subtype, the aggressive CLL subtype, and DLBCL using a Kruskal-Wallis test. All p values were adjusted after the Bonferroni correction. ROC analyses for significant CTTA features were performed to determine cut-off values for differentiation between the groups.
RESULTS: Compared with DLBCL of RS, CTTA of the entire CLL group showed significant differences of entropy heterogeneity (p < 0.001), mean intensity (p < 0.001), mean average (p = 0.02), and number non-uniformity gray-level dependence matrix (NGLDM) (p = 0.03). Indolent CLL significantly differed for entropy (p < 0.001), uniformity of heterogeneity (p = 0.02), mean intensity (p < 0.001), and mean average (p = 0.01). Aggressive CLL showed significant differences in mean intensity (p = 0.04). For differentiation between CLL and DLBCL of RS, cut-off values for mean intensity and entropy of heterogeneity were defined (e.g., 6.63 for entropy heterogeneity [aggressive CLL vs. DLBCL]; sensitivity 0.78; specificity 0.63).
CONCLUSIONS: CTTA features of ultrastructure and vascularization significantly differ in CLL compared with that in DLBCL of Richter syndrome, allowing complementary to visual features for noninvasive differentiation by contrast-enhanced CT.
KEY POINTS: • Richter transformation of CLL into DLBCL results in structural changes in lymph node architecture and vascularization that can be detected by CTTA. • First-order CT textural features including intensity and heterogeneity significantly differ between both indolent CLL and aggressive CLL and DLBCL of Richter syndrome. • CT texture analysis allows for noninvasive detection of Richter syndrome which is of prognostic value.

Chen D, Zhan Y, Peng J, Yao F
CD5-negative chronic lymphocytic leukemia/small lymphocytic lymphoma in a patient with gastrointestinal mantle cell lymphoma: an unusual case report.
Onco Targets Ther. 2019; 12:2937-2941 [PubMed] Free Access to Full Article Related Publications
Richter's syndrome, the development of high-grade non-Hodgkin lymphoma in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), may be triggered by viral infections (eg, Epstein-Barr virus infection). Herein, we report an unusual case of CD5-negative CLL/SLL patient with gastrointestinal mantle cell lymphoma (MCL) and hepatitis B virus infection. CLL/SLL was diagnosed based on lymph node immunohistochemistry and bone marrow pathology. This patient was treated with seven cycles of multi-agent chemotherapy. During treatment, the hepatitis B viruses were activated. Then, after 20 months of antiviral treatment with entecavir, he developed abdominal discomfort and abdominal lymphadenopathy and was diagnosed with MCL based on intestinal biopsy. This work indicates that the hepatitis B virus in patients with CLL/SLL may accelerate the progress or transformation to MCL.

Appleby N, Eyre TA, Cabes M, et al.
The STELLAR trial protocol: a prospective multicentre trial for Richter's syndrome consisting of a randomised trial investigation CHOP-R with or without acalabrutinib for newly diagnosed RS and a single-arm platform study for evaluation of novel agents in relapsed disease.
BMC Cancer. 2019; 19(1):471 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Transformation of chronic lymphocytic leukaemia (CLL) to diffuse large B-cell lymphoma (DLCBL) type Richter's syndrome (RS) carries a dismal prognosis. Standard-of-care chemoimmunotherapy for de novo RS is inadequate with median survival of less than one year. Patients are frequently elderly or have co-morbidities limiting dose-intense chemotherapy. Treatment of relapsed/refractory (R/R) RS and RS emerging after CLL-directed therapy represent urgent unmet clinical needs. Agents targeting Bruton's tyrosine kinase (BTK) deliver improved outcomes for patients with high-risk CLL and expand effective treatments to frailer patients. Acalabrutinib is an oral, second-generation BTK inhibitor with a favourable toxicity profile and demonstrated activity in CLL and B-cell lymphomas. Combination of acalabrutinib with standard-of-care CHOP-R chemoimmunotherapy offers a sound rationale to test in a prospective trial for de novo RS.
METHODS: The prospective multicentre STELLAR study is designed in two elements, consisting of a randomised study to evaluate the safety and activity of CHOP-R chemoimmunotherapy in combination with acalabrutinib in newly diagnosed RS and single-arm studies of novel agents for other RS patient cohorts. Eligible patients with newly diagnosed DLBCL-type RS are randomised between six cycles of CHOP-R therapy and six cycles CHOP-R plus acalabrutinib, followed by acalabrutinib maintenance. The primary endpoint of the randomised component is progression free survival (PFS). Cohort 1 enrols RS patients with progressive disease following chemoimmunotherapy for acalabrutinib monotherapy. Patients with RS diagnosed while on ibrutinib may enrol in Cohort 2, a single-arm study of CHOP-R plus acalabrutinib. The primary endpoint for the single-arm studies is overall response rate (ORR). Secondary endpoints for all cohorts are overall survival (OS), quality of life and proportion of patients proceeding to stem cell transplantation. The study will be accompanied by exploratory analysis of the mutational landscape of RS and the relationship between dynamic changes in sequential circulating tumour DNA samples and clinical outcomes.
DISCUSSION: The STELLAR randomised trial evaluates the role of CHOP-R plus acalabrutinib in newly diagnosed RS patients. The single-arm platform studies enable the incorporation of promising novel therapies into the protocol. The STELLAR study has potential to identify novel biomarkers of treatment response in this high-risk malignancy.
TRIAL REGISTRATION: EudraCT: 2017-004401-40 , registered on the 31-Oct-2017. IRSCTN: https://www.isrctn.com/ISRCTN52839057 , registered on the 04-Mar-2019. ClinicalTrials.gov : NCT03899337 , registered on 02-April-2019.

Xia L, Wang Y, Li T, et al.
The clinical study on treatment of CD19-directed chimeric antigen receptor-modified T cells in a case of refractory Richter syndrome.
Cancer Med. 2019; 8(6):2930-2941 [PubMed] Free Access to Full Article Related Publications
Richter syndrome (RS) indicates the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma (mostly DLBCL). Richter syndrome is a rare complication with an aggressive clinical course, bearing an unfavorable prognosis. Currently, there is no effective treatment for it. As a novel cellular-based immune therapy, chimeric antigen receptor-modified T (CART) cells treatment is gradually used in treating hematological malignancies, especially in CD19

Drozd-Sokołowska J, Zaucha JM, Żółtak T, et al.
Hodgkin lymphoma transformation of chronic lymphocytic leukemia-A real life data from the Polish Lymphoma Research Group.
Hematol Oncol. 2019; [PubMed] Related Publications
Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to Hodgkin lymphoma (HL) is a rare and unexpected event in the course of the disease and data on this phenomenon is still limited. To better understand the clinical and histological characteristics and the outcomes of HL variant of RT (HvRS) the Polish Lymphoma Research Group performed a nationwide survey which identified 22 patients with histologically proven HvRS diagnosed between 2002 and 2016. There were 16 (73%) males. The median age at CLL/SLL and HvRS diagnosis was 59 (39-77) and 64 (40-77) years, respectively. The median interval between CLL/SLL and HvRS diagnosis was 38 months (range: 0-187). All patients had an advanced stage HL, and majority, 17 (77%), presented with B symptoms. The predominant subtypes of HL were nodular sclerosis (12; 55%) and mixed cellularity (9; 41%). Eighteen patients received non-palliative treatment, including 13 who received driamycin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen first line. Objective response was: 50%, with 33% complete remissions (61% and 46% for ABVD, respectively). Median overall survival reached 13.3 months (95% CI, 3.7-NA). The only adverse prognostic factor for survival was a higher number (≤1 versus ≥2) of prior lines of treatment given for CLL/SLL with HR 3.57 (95% CI, 1.16-10.92). We conclude, HvRS harbors a poor prognosis, especially in patients heavily pretreated for CLL/SLL. Response to standard first-line anti-HL chemotherapy is unsatisfactory, and new agents should be tested to improve the outcome.

Lenartova A, Randen U, Johannesen TB, Tjønnfjord GE
Richter syndrome epidemiology in a large population based chronic lymphocytic leukemia cohort from Norway.
Cancer Epidemiol. 2019; 60:128-133 [PubMed] Related Publications
BACKGROUND: Transformation to aggressive lymphoma (Richter syndrome, RS) occurs in a substantial subset of patients who must discontinue targeted therapy for chronic lymphocytic leukemia (CLL). RS has an extremely poor prognosis.
METHODS: Using the nation-wide database of The Cancer Registry of Norway of 7664 CLL patients registered between 1953-2012, we identified 107 patients experiencing RS.
RESULTS: Seventy seven (72%) of RS patients were identified among 2631 CLL patients diagnosed between 2003-2012; diffuse large B-cell lymphoma (DLBCL) was identified in 65 (84%), Hodgkin lymphoma (HL) in 12 (16%) patients and the diagnosis was confirmed in 50 (65%) available biopsy specimens. The incidence rate in this period was 4.7/1000 person-years (95% CI: 3.8-5.9). The median survival from CLL diagnosis was 1.7 years (95% CI: 0.34-2.3) for RS patients while it was 10.3 years (95% CI: 9.5-10.9) for the remaining CLL patients. Male gender predominated among RS patients (69%) compared to CLL population (58%) and RS patients were diagnosed with CLL at a significantly younger age than the remaining patients (65 vs. 72 years). Median time from diagnosis of CLL to RS was 2 years (Range, 0-13 years). No CLL treatment was administered in 25 (33%) patients prior RS diagnosis; a median of 1 treatment line was administered to pretreated patients. The median duration of survival after RS diagnosis was 27 months (95% CI; 9-88).
CONCLUSIONS: Collectively, RS was a rare complication of CLL in the chemoimmunotherapy era, occurred early in the CLL course in younger, and both treatment naïve and pretreated patients, and shortened survival substantially.

Bagacean C, Zdrenghea M, Saad H, et al.
Rapid and complete response to idelalisib in a case of Richter syndrome.
Onco Targets Ther. 2019; 12:1181-1184 [PubMed] Free Access to Full Article Related Publications
Richter syndrome (RS) is an aggressive lymphoma arising on the back of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and is the most common B-cell malignancy in the Western world. In the majority of cases, RS presents an activated B cell (ABC) phenotype of diffuse large B-cell lymphoma (DLBCL). From the therapeutic point of view, selective inhibition of PI3Kδ with idelalisib represents a valuable addition to available treatment options for patients with CLL/SLL, many of whom do not respond to or cannot tolerate chemoimmunotherapy. However, to our knowledge, there have been no prospective studies evaluating idelalisib efficacy in a DLBCL-ABC form of RS. Here, we present a case of a DLBCL-ABC form of RS achieving a complete response at 3 weeks after initiating idelalisib and rituximab therapy for six cycles. This response was maintained during the idelalisib monotherapy, but the patient relapsed rapidly after treatment was withdrawn, because of a grade three immune colitis that developed at 10 months of treatment. This report demonstrates that idelalisib is highly effective in RS and provides an attractive option in this aggressive disease. This agent could meet an unmet need by providing a treatment option with a tolerable safety profile for elderly patients with RS.

Rezvani S, Tominna M, Al-Katib S, et al.
Lymphomatoid Granulomatosis in a Patient with Chronic Lymphocytic Leukemia and Rapidly Progressing Peribronchovascular Pulmonary Infiltrates.
Case Rep Pulmonol. 2019; 2019:9870494 [PubMed] Free Access to Full Article Related Publications
Lymphomatoid granulomatosis (LG) is an EBV-associated angiodestructive lymphoproliferative disease with multiorgan involvement that predominantly affects the lungs. We present a case of a 72-year-old man with a history of chronic lymphocytic leukemia who presented with upper respiratory symptoms and multiple erythematous skin papules. Chest CT showed ill-defined, irregular solid pulmonary nodules with peripheral ground-glass opacities in a peribronchovascular distribution. The differential for this pattern of lung disease is vast which includes but is not limited to infection, vasculitis, sarcoidosis, lymphoma, and Kaposi sarcoma. Subsequent PET/CT showed rapid progression of lung opacities and marked FDG uptake of pulmonary opacities and skin nodules, which raised the question of Richter syndrome. Wedge biopsy under video-assisted thoracoscopic surgery was performed. Pathology showed an extensive lymphoid infiltrate involving lymphatic and bronchovascular bundles and consisting of a mixture of large lymphocytes and inflammatory cells. Special stains showed that the large lymphocytes expressed B-cell markers and EBV virus. Overall, the findings were consistent with LG.

Puła B, Salomon-Perzyński A, Prochorec-Sobieszek M, Jamroziak K
Immunochemotherapy for Richter syndrome: current insights.
Immunotargets Ther. 2019; 8:1-14 [PubMed] Free Access to Full Article Related Publications
Richter syndrome (RS) is recognized as the development of a secondary and aggressive lymphoma during the clinical course of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Most of such histological transformations are from RS to diffuse large B-cell lymphoma (DLBCL-RS, 90%) and Hodgkin's lymphoma (HL-RS, 10%). Histopathological examination is a prerequisite for diagnosis. It is crucial to assess the relationship between the RS clone and the underlying CLL/SLL because clonally related DLBCL-RS has a poor outcome, while clonally unrelated cases have a prognosis similar to de novo DLBCL. An anti-CD20 antibody-based immunochemotherapy is hitherto the frontline treatment of choice for DLBCL-RS; nonetheless, the results are unsatisfactory. Allogeneic stem cell transplantation should be offered to younger and fit patients as a consolidative treatment; however, the majority of the patients may not be qualified for this procedure. The HL-RS transformation has better outcomes than those of DLBCL-RS and can effectively be treated by the adriamycin, bleomycin, vinblastine, and dacarbazine regimen. Although novel agents are currently being investigated for RS, immunochemotherapy nevertheless remains a standard treatment for DLBCL-RS.

Allan JN, Furman RR
Current trends in the management of Richter's syndrome.
Int J Hematol Oncol. 2018; 7(4):IJH09 [PubMed] Free Access to Full Article Related Publications
Richter's syndrome (RS) is a life-threatening complication of chronic lymphocytic leukemia (CLL). While previous research has increased our knowledge on the distinct evolutionary patterns of RS and provided a deeper understanding of the risk factors and molecular events predisposing to transformation, there remain few targetable aberrations and treatment is largely ineffective. The ability to obtain deeper remissions, without selecting for deletion 17p, by using novel B-cell receptor (BCR) antagonists and bcl2 inhibition might lead to a decrease in the incidence of RS, but these agents have done little to significantly change outcomes when incorporated into treatment regimens for RS. In this review we highlight the current landscape of molecular lesions specific to RS, review the data on historical treatment options, and look to the horizon for potential opportunities in the future.

Auditeau C, Lambotte O, Feriel J, et al.
A composite lymphoma combining a Hodgkin lymphoma and a marginal zone lymphoma transformed into a diffuse large B-cell lymphoma.
Clin Case Rep. 2018; 6(12):2341-2346 [PubMed] Free Access to Full Article Related Publications
Composite lymphoma is defined as the occurrence of two or more distinct lymphoma types in a single anatomic site. We report a case of Richter syndrome with both Hodgkin lymphoma and non-Hodgkin lymphoma in the bone marrow. This diagnostic was suspected because of discrepancies between histological and cytological results.

Müller DJ, Wirths S, Fuchs AR, et al.
Loss of NFAT2 expression results in the acceleration of clonal evolution in chronic lymphocytic leukemia.
J Leukoc Biol. 2019; 105(3):531-538 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) can be defined as a clonal expansion of B cells with stereotypic BCRs. Somatic hypermutation of the BCR heavy chains (IGVH) defines a subgroup of patients with a better prognosis. In up to 10% of CLL cases, a transformation to an aggressive B cell lymphoma (Richter's syndrome) with a dismal prognosis can be observed over time. NFAT proteins are transcription factors originally identified in T cells, which also play an important role in B cells. The TCL1 transgenic mouse is a well-accepted model of CLL. Upon B cell-specific deletion of NFAT2, TCL1 transgenic mice develop a disease resembling human Richter's syndrome. Whereas TCL1 B cells exhibit tonic anergic BCR signaling characteristic of human CLL, loss of NFAT2 expression leads to readily activated BCRs indicating different BCR usage with altered downstream signaling. Here, we analyzed BCR usage in wild-type and TCL1 transgenic mice with and without NFAT2 deletion employing conventional molecular biology techniques and next-generation sequencing (NGS). We demonstrate that the loss of NFAT2 in CLL precipitates the selection of unmutated BCRs and the preferential usage of certain VDJ recombinations, which subsequently results in the accelerated development of oligoclonal disease.

Lavalle M, Minordi LM, Hohaus S, et al.
Richter Syndrome Presenting With Colon Localization.
Clin Nucl Med. 2019; 44(2):e87-e89 [PubMed] Related Publications
A 75-year-old man, who had been diagnosed with small lymphocytic lymphoma with cervical localization, underwent F-FDG PET/CT with iodinated contrast medium due to the appearance of cervical swelling suspected of illness relapse. PET/CT revealed intense F-FDG uptake in multiple cervical and subdiaphragmatic lymph nodes and in the left parotid. Moreover, diffuse uptake and wall thickening of the colon were evident; endoscopy with biopsy revealed a diffuse large B-cell lymphoma. Transformation into a more aggressive lymphoma occurs in 2% to 8% of small lymphocytic lymphoma, the so-called Richter syndrome. Extranodal localization in the sigmoid colon is an extremely rare site for transformed lymphoma.

Van Roosbroeck K, Bayraktar R, Calin S, et al.
The involvement of microRNA in the pathogenesis of Richter syndrome.
Haematologica. 2019; 104(5):1004-1015 [PubMed] Free Access to Full Article Related Publications
Richter syndrome is the name given to the transformation of the most frequent type of leukemia, chronic lymphocytic leukemia, into an aggressive lymphoma. Patients with Richter syndrome have limited response to therapies and dismal survival. The underlying mechanisms of transformation are insufficiently understood and there is a major lack of knowledge regarding the roles of microRNA that have already proven to be causative for most cases of chronic lymphocytic leukemia. Here, by using four types of genomic platforms and independent sets of patients from three institutions, we identified microRNA involved in the transformation of chronic lymphocytic leukemia to Richter syndrome. The expression signature is composed of miR-21, miR-150, miR-146b and miR-181b, with confirmed targets significantly enriched in pathways involved in cancer, immunity and inflammation. In addition, we demonstrated that genomic alterations may account for microRNA deregulation in a subset of cases of Richter syndrome. Furthermore, network analysis showed that Richter transformation leads to a complete rearrangement, resulting in a highly connected microRNA network. Functionally, ectopic overexpression of miR-21 increased proliferation of malignant B cells in multiple assays, while miR-150 and miR-26a were downregulated in a chronic lymphocytic leukemia xenogeneic mouse transplantation model. Together, our results suggest that Richter transformation is associated with significant expression and genomic loci alterations of microRNA involved in both malignancy and immunity.

Carrión-Valencia A, Rodríguez-Talavera J, Ballesta-Martínez B
Extranodal Richter's syndrome of the urinary bladder.
Indian J Urol. 2018 Oct-Dec; 34(4):297-299 [PubMed] Free Access to Full Article Related Publications
Lymphomas of the urinary bladder are rare and can be primary or secondary. The latter group includes Richter's Syndrome-which is a transformation of a chronic low-grade lymphoproliferative syndrome into a common type of non-Hodgkin lymphoma, most commonly localized in the lymph nodes. We report a case of an 84-year-old male, former-smoker with a history of low-grade chronic lymphocytic leukemia, treated with chemotherapy, with a recurrence of the disease to retroperitoneal and iliac lymph nodes, splenomegaly, and thickening of the bladder wall. The hematologist consulted us because of hematuria with coexistent bilateral obstructive uropathy. We performed transurethral resection of the bladder which revealed secondary lymphoma in the bladder, probably the result of a high-grade transformation from chronic leukemia, a very rare location of this transformation.

Xu L, Song JC, Sun XH, et al.
Richter's syndrome of the central nervous system diagnosed concurrently with chronic lymphocytic leukaemia: A case report and literature review.
Medicine (Baltimore). 2018; 97(41):e12701 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Central nervous system (CNS) infiltration of Richter's syndrome (RS) is rare and only a few cases were discussed. Of these published cases, either they were accompanied with lymph node involvement or with a history of chronic lymphocytic leukemia (CLL). To our knowledge, this is the first published case of RS of the brain and meninges diagnosed concurrently with CLL in the absence of any evidence of lymphoma outside of the CNS.
PATIENT CONCERNS: A 67-year-old female presented with slurred speech, headache, and left-sided hemiparesis. Magnetic resonance imaging of the brain revealed an irregular lesion 30 mm in diameter in the right parietal lobe. The mass was totally removed and pathology revealed diffuse large B-cell lymphoma (DLBCL) of non-germinal center type by Hans' classification. The patient's leukocyte count was 12.1 × 109/L (76.9% lymphocytes), and fluorescence-activated cell sorting (FACS) analysis of blood revealed a clonal B-cell population (36.75% leukocytes) corresponding to the immunological CLL profile (Matutes score of 5/5). Bone marrow (BM) aspiration and biopsy also indicated CLL. The analysis of immunoglobulin heavy chain gene (IGH) and kappa chain gene (IGK) in the patient's BM and CNS tissue indicated that the DLBCL of the brain was derived from the CLL clone.
DIAGNOSES: RS of the CNS diagnosed concurrently with CLL.
INTERVENTIONS: The patient received intravenous chemotherapy (6.0 g methotrexate) and intrathecal chemotherapy (10 mg methotrexate, 50 mg cytarabine, 5 mg dexamethasone).
OUTCOMES: The patient returned to our department with left-sided hemiparesis and headache 2 weeks after the chemotherapy. Repeat MRI showed progression of the brain lesion. Her general condition deteriorated significantly with confusion and high fever, and she died within a few days at only 10 weeks after the onset of symptoms.
LESSONS: The survival of CNS-RS patients is very poor and and is always complicated with multiple and different genetic alterations. Because of chemotherapy insensitivity, a multidisciplinary treatment including surgery and radiotherapy together with novel agents may be an option to improving patient outcomes.

Balatti V, Tomasello L, Rassenti LZ, et al.
Blood. 2018; 132(20):2179-2182 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. It is characterized by the accumulation of CD19

Jurj A, Pop L, Petrushev B, et al.
Exosome-carried microRNA-based signature as a cellular trigger for the evolution of chronic lymphocytic leukemia into Richter syndrome.
Crit Rev Clin Lab Sci. 2018; 55(7):501-515 [PubMed] Related Publications
Even if considered a cumulative and not a proliferative CD5+ B-cell neoplasm, chronic lymphocytic leukemia (CLL) has a proliferation rate higher than that recognized earlier, especially in the lymphoid tissues. Some patients with CLL develop a clinical syndrome entitled Richter syndrome (RS). Understanding CLL genetics and epigenetics may help to elucidate the molecular basics of the clinical heterogeneity of this type of malignancy. In the present project we aimed to identify a microRNA species that can predict the evolution of therapy-resistant CLL towards RS. In the first phase of our study, microRNA-19b was identified as a possible target, and in the second phase, we transfected three different CLL cell lines with microRNA-19b mimic and inhibitor and assessed the potential role on leukemia cells in vitro. The mechanism by which miR-19b acts were identified as the upregulation of Ki67 and downregulation of p53. This was further supported through RT-PCR and western blotting on CLL cell lines, as well as by next generation sequencing on two patients diagnosed with CLL that evolved into RS.

Godfrey J, Leukam MJ, Smith SM
An update in treating transformed lymphoma.
Best Pract Res Clin Haematol. 2018; 31(3):251-261 [PubMed] Related Publications
Indolent lymphomas typically have a prolonged course and favorable prognosis. Recent data support survival times that can reach several decades, even if periodic treatment is needed to manage symptoms or stabilize disease. However, all indolent lymphomas have the potential to undergo transformation to an aggressive phenotype, clinically characterized by a rapid progression of adenopathy, new-onset constitutional symptoms, or laboratory abnormalities, and the immediate need for therapeutic intervention. The most common scenario is transformation of follicular lymphoma to either diffuse large B-cell lymphoma or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocations; however, other indolent subtypes such as marginal zone lymphoma, lymphoplasmacytic lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, or even nodular lymphocyte predominant Hodgkin lymphoma, can undergo similar histologic transformation. The prognosis of transformed lymphomas has historically been quite poor, but there is ample evidence this is changing in the rituximab era. This article will provide a review of transformed lymphomas with an emphasis on treatment and the nuances of diagnosis and clinical management. Unless otherwise specified, all discussion in this review pertains to transformed follicular lymphoma which is the more common scenario and the subtype with the most robust data. In many cases, this information can be extrapolated and applied to other indolent histologies (i.e. transformed marginal zone lymphoma); however, several other clinical scenarios, such as Richter's transformation and "double hit" transformations, warrant a distinct discussion and will be reviewed separately.

Wąsik-Szczepanek E, Szymczyk A, Szczepanek D, et al.
Richter syndrome: A rare complication of chronic lymphocytic leukemia or small lymphocytic lymphoma.
Adv Clin Exp Med. 2018; 27(12):1683-1689 [PubMed] Related Publications
BACKGROUND: Richter's syndrome (RS) is a rare complication with an unfavorable prognosis, in which chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) transform into a more aggressive type of lymphoma, most commonly into diffuse large B cell lymphoma (DLBCL) or less often into Hodgkin's lymphoma (HL).
OBJECTIVES: The objective of this research paper was to present a retrospective analysis of patients with CLL/SLL whose disease transformed into RS.
MATERIAL AND METHODS: The study included 217 patients (100 women and 107 men) with CLL/SLL diagnosed in the years 2006-2015 at the Department of Hematooncology and Bone Marrow Transplantation of the Medical University of Lublin, which transformed into RS. We analyzed clinical, laboratory, immunophenotypic (ZAP-70 and CD38 expression), histopathological, and genetic data (del(17p), del(11q)), which was collected at the time of CLL/SLL diagnosis, and some which was collected at the time of transformation.
RESULTS: Richter's syndrome was diagnosed in 4.6% of all CLL and SLL patients. The group of patients with RS consisted of 9 patients with primary CLL and 1 patient with a diagnosis of SLL (8 patients with transformation into DLBCL and 2 patients with transformation into HL). Leukemic lymphocytes showed evidence of peripheral blood lymphocyte membrane expression of ZAP70+/CD38+ (1 patient), of ZAP-70+/CD38- (3 patients), of ZAP-70-/CD38- (1 patient), and of ZAP-70-/CD38+ (5 patients). The deletion of 11q (del(11q)) was documented in 2 patients. In 4 cases, the location of RS was extremely rare (the thyroid gland, liver, skin, bladder, and central nervous system).
CONCLUSIONS: Richter's syndrome is a rare, but probable complication of CLL/SLL with an unfavorable prognosis, and it should be taken into account at every stage of the disease, particularly when the course of the disease is aggressive.

Garces S, Khoury JD, Kanagal-Shamanna R, et al.
Chronic lymphocytic leukemia with proliferation centers in bone marrow is associated with younger age at initial presentation, complex karyotype, and TP53 disruption.
Hum Pathol. 2018; 82:215-231 [PubMed] Related Publications
The presence of expanded proliferation centers (PCs) in lymph nodes involved by chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma has been associated with adverse clinical outcomes, but the frequency and significance of PCs in bone marrow (BM) remain unclear. The study group included 36 patients with BM involvement by CLL in which PCs were present. We compared this group with 110 randomly selected BM samples involved by CLL without morphologically discernable PCs. Patients with PCs in BM were younger (median age, 53 years [range,18-71 years] versus 58 years [range, 31-82 years]; P = .007), more frequently experienced B symptoms (27.8% versus 8.2%, P = .0076), more often had Rai stage IV disease (30.6% versus 17.3%, P = .02) and higher serum lactate dehydrogenase (P = .0037) and β

Ge H, Wu X, Shen J, et al.
A case report of extranodal NK/T-cell lymphoma in patient with chronic lymphocytic leukemia.
Medicine (Baltimore). 2018; 97(30):e11619 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
RATIONALE: Chronic lymphocytic leukemia often results in secondary tumors, the most common being large B cell lymphoma known as Richter syndrome, followed by extranodal NK/T-cell lymphoma (nasal type) is extremely rare.
PATIENT CONCERNS: A chronic lymphocytic leukemia patient presented with nasal congestion.
DIAGNOSES: Nasal endoscopy identified a left nasal mass, and the pathology suggested extranodal NK/T-cell lymphoma (nasal type).
INTERVENTIONS: The patient received a course of chemotherapy.
OUTCOMES: Pneumonia and coagulopathy occurred after chemotherapy, and the patient died shortly thereafter.
LESSONS: It is essential to recognize the transformation of disease earlier in chronic lymphoblastic leukemia patient.

Behdad A, Griffin B, Chen YH, et al.
PD-1 is highly expressed by neoplastic B-cells in Richter transformation.
Br J Haematol. 2019; 185(2):370-373 [PubMed] Related Publications

Rogers KA, Huang Y, Dotson E, et al.
Use of PD-1 (PDCD1) inhibitors for the treatment of Richter syndrome: experience at a single academic centre.
Br J Haematol. 2019; 185(2):363-366 [PubMed] Related Publications

Visentin A, Imbergamo S, Scomazzon E, et al.
BCR kinase inhibitors, idelalisib and ibrutinib, are active and effective in Richter syndrome.
Br J Haematol. 2019; 185(1):193-197 [PubMed] Related Publications

Federmann B, Mueller MR, Steinhilber J, et al.
Diagnosis of Richter transformation in chronic lymphocytic leukemia: histology tips the scales.
Ann Hematol. 2018; 97(10):1859-1868 [PubMed] Related Publications
Development of diffuse large B-cell lymphoma in chronic lymphocytic leukemia, so-called Richter transformation (RT), occurs in 2-5% of patients and is associated with poor outcome. The clinical features of RT are fairly non-specific and unable to discriminate transformation from other mimics. In case of clinically suspected RT, a CT/MRT is recommended, and FDG-PET/CT may help to select the site of biopsy. Radiological features suggestive of RT have been defined, but there are only limited data about their predictive value, and histological confirmation is still considered the gold standard for RT diagnosis. We retrospectively analyzed 34 patients with clinically suspected RT and available radiological and histological data. A histopathological diagnosis of RT with concordant clinical and radiological findings was obtained in 13 patients. In 18 patients, CT did not show features of transformation, concordant with lack of RT in the biopsy. Of interest, a distinct lymphoma other than DLBCL was identified in two of these cases. A false-positive radiological diagnosis of RT was rendered in two patients, including a case of Herpes simplex virus lymphadenitis. In conclusion, our findings confirm the central role of tissue biopsy in the diagnostic work up in case of clinically suspected RT.

Imataki O, Uemura M
B-chronic lymphocytic leukemia showed triple transformation, to diffuse large B cell, CD20-negative, and T-cell neoplasm during ofatumumab treatment: a case report.
BMC Clin Pathol. 2018; 18:5 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
Background: Chronic lymphocytic leukemia (CLL) is a mature lymphoid neoplasm currently categorized as an indolent type of malignant lymphoma. CLL progresses slowly over years, but it eventually transforms to a more aggressive lymphoma such as the diffuse large B-cell (DLBCL) type, also known as Richter's syndrome.
Case presentation: We treated a 69-year-old Japanese male who was histologically diagnosed with Richter's syndrome after 6 years of CLL. His lymphadenopathy had systemically progressed for years, with lymphocyte counts of less than 10,000 cells/μL and a disease status of Rai classification stage I and Binet classification B. He had high fever and hepatosplenomegaly upon Richter's transformation. The patient was treated with ofatumumab for refractory CLL, which relieved his febrile lymphadenopathy. He received a total of 11 ofatumumab courses and achieved partial remission. On the day of the 12th course of ofatumumab, his disease relapsed with febrile lymphadenopathy. Computed tomography revealed multiple liver masses and systemic lymphadenopathy, while a liver biopsy confirmed T-cell lymphoma. Concomitantly, CD20-lacking CLL cells were detected in his peripheral blood and bone marrow, and pathological examination of his left cervical lymph node biopsy showed CD20-positive DLBCL. The final diagnosis was three different types of lymphoma pathologies: (1) CD20-positive DLBCL of the lymph nodes, (2) CD20-lacking CLL of the peripheral blood and bone marrow, and (3) peripheral T-cell lymphoma (PTCL) of the liver. He received intravenous and oral dexamethasone therapy as palliative care. He died because of the rapid progression of abdominal masses 2 months after the diagnosis of triple transformation CLL. An autopsy revealed aggressive PTCL with aggressive systemic involvement of the liver, spleen, gall bladder, pericardium, bone marrow, and mediastinal-paraaortic-intraceliac lymph nodes. T-cell receptor study of an autopsy specimen supported the diagnosis of PTCL that spread to the intraceliac organs and lymph nodes. We concluded that his pathogenicity progressed to a mixture of triple lymphoma as a result of double malignant transformations, which included PTCL from CLL, CD20-negative CLL, and CD20-positive DLBCL by Richter's transformation.
Conclusions: Our case provides information on the biology of CLL, to transform from a low-grade chemosensitive status to a malignant chemoresistant status.

Alderuccio JP, Mackrides N, Chapman JR, et al.
Rapid complete response to blinatumomab as a successful bridge to allogeneic stem cell transplantation in a case of refractory Richter syndrome.
Leuk Lymphoma. 2019; 60(1):230-233 [PubMed] Related Publications

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