Chronic Lymphoid Leukemia Initially Diagnosed in Richter Transformation Phase: A Case Report from the Clinical Hematology Department, Cocody University Hospital

Background: Richter syndrome is a rare complication that occurs in patient with chronic lymphoid leukemia (CLL). It reflects the transformation of CLL into an aggressive lymphoma, the most common pathological phenotype of which is diffuse large B-cell lymphoma (DLBCL) and, rarely, Hodgkin's disease. It is usually discovered during the late stages of untreated CLL and/or CLL that does not respond to conventional first-line immunochemotherapy. the new method of diagnosis such immunohistochemistry immunophenotype contribute to the better identification for better treatment We therefore report the case of a simultaneous diagnosis of Richter syndrome in a young black patient.

Case report: This paper reports the case of a 49-year-old female patient with no medical or surgical history who was admitted for investigation of peripheral lymphocytosis associated with subacute, asymmetrical, non-inflammatory lymphadenopathy. Simultaneous etiological investigations led to a diagnosis of de novo CLL, which was immediately reclassified as a high-grade diffuse large B-cell lymphoma. Poor prognostic factors included a short doubling time and CD38 positivity, but 17p deletion was absent. The patient achieved complete remission under the R-EPOCH protocol.

Conclusion: Based on this observation, we highlight the possibility of rapid onset and simultaneous diagnosis of Richter syndrome during chronic lymphocytic leukemia.

Chronic lymphoid CLL leukemia is a malignant hematologic disorder characterized by clonal proliferation and accumulation of mature B lymphocytes. It has long been considered a disease of patients over 65 years of age [1]. In its evolution, in addition to infectious complications related to hypogammaglobulinemia, CLL is frequently complicated by immunological cytopenias and sometimes progresses toward transformation into a lymphoma, hence the term Richter syndrome. This syndrome is defined by the appearance of an aggressive high-grade lymphoma (diffuse large B- cell lymphoma and, more rarely, Hodgkin lymphoma) in a patient with chronic lymphocytic leukemia (CLL). Its incidence is estimated between 0.5-1% of chronic lymphocytic leukemia cases per year and is associated most of the time with a poor prognosis [2]. Patients with Richter syndrome commonly present two (2) distinct types of somatic abnormalities: an alteration of the TP53 gene (50% of cases) which may or may not be associated with deletion of the CDKN2A locus (del 19p), the second associates’ trisomy 12 with a NOTCH1 mutation (30% of cases). Additionally, MYC abnormalities are also found in Richter syndrome. However, it es established that 2/3 of patients with Richter syndrome during CLL do not present any mutation of the immunoglobulin heavy chain variable region gene (IGVH), unlike de novo diffuse large B- cell lymphomas where the profile is classically mutated IGHV [3]. Generally, the clinical suggestive presentation of Richter syndrome is Quite pronounced, characterized by the presence of B symptoms and a notable and asymmetrical increase in lymph node size (≥4 cm). However, a lymph node biopsy with immunohistochemical study es always necessary to identify the phenotypic appearance of the lymphoma and its aggressive character, which will be determined by the proliferation index (elevated Ki67). Therapeutic options in patients with Richter syndrome depend on the presence or absence of patient- specific comorbidities, the nature of chromosomal aberrations on cytogenetics, the type of molecular mutation, drug interactions, but also their clinical status at diagnosis. Therefore, each patient may be eligible for at least one therapeutic option, depending on their economic capacity. However, despite therapeutic advances (immunochemotherapy), the complete Remission rate remains low in patients with Richter transformation, hence the interest in initiating targeted therapy molecules (anti-BCL2, Bruton tyrosine kinase inhibitor, anti-PD1, CAR T cells).

In this work, we describe the possibility of a Richter syndrome diagnosis at the same time as chronic lymphocytic leukemia within a short clinical evolution time of symptoms (less than 6 months).

This concerns Mrs. BN, aged 49, resident in Abidjan, a teacher by profession, seen in hematology consultation on February 12, 2025 for investigation of hyperleukocytosis with lymphocytic predominance associated with feverish lymphadenopathy of acute evolution (December 2024). Personally, she had no medical or surgical history; However, her father died from a prostatic neoplasm of unspecified nature. In terms of gynecological-obstetrical history, she was gravida 4, para 2 with 2 previous miscarriages for a poly- fibroid uterus.

Clinical presentation: On admission, we had a patient with average general condition (WHO performance status 2). She had the following general signs: fever at 38.2°C and weight loss of 9 kg. As tumor manifestations, she had multiple cervical lymphadenopathies, bilateral, asymmetrical, located in the suboccipital, retroauricular, laterocervical, and supraclavicular regions, measuring 1.5 to 4.5 cm, painless, firm, mobile and non- fistulizing. Presence of a 4 cm left axillary lymphadenopathy and 2 bilateral symmetrical inguinal lymphadenopathies of 2 cm, painless, firm, mobile and without tendency to fistulization. During this clinical examination, there was no hepatosplenomegaly nor symptoms of anemia intolerance or hemorrhagic symptoms.

Diagnostic workup

On the Blood count, peripheral lymphocytosis was found at 61,061/mm³ associated with bicytopenia consisting of anemia (hemoglobin at 10.01 g/dl) and thrombocytopenia (platelets at 117 G/L). In addition, there was also peripheral monocytosis. The blood smear showed peripheral lymphocytosis of 88% and presence of Gumprecht shadows in the cells. Lymphocytic immunophenotyping was in favor of chronic lymphocytic leukemia (CLL) with a Matutes score of 5/5. Given the tumor lymph node infiltration (size, asymmetry and involvement of several territories), a cervical lymph node biopsy was performed with histological and immunohistochemical study. The histological study showed lymph node tissue with destroyed architecture by a lymphoid tumor proliferation made of small and medium- sized cells with hyperchromatic nuclei, sometimes vesicular and nucleolated . However, the phenotypic markers on immunohistochemistry were in favor of a non-germinal center diffuse large B- cell lymphoma: Ki67 (85%), CD20 (+), CD45 (+), BCL2 (+), BCL6 (-), MUM1 (-), CD10 (-), CD30 (-), CD15 (-), CKAE1/AE3 (-). CD5 and CD3 identified reactive lymphocytes.

Prognosis evaluation

Our patient was evaluated clinically and biologically (prognostic and pretherapeutic workup) to search for possible comorbidities. Following this evaluation, she had signs of clinical progression (fever, weight loss) and biological progression (LDH at 1581 IU/L and beta-2 microglobulin at 9.05 mg/L). A cervico-thoraco- abdomino - pelvic CT scan performed in the patient showed splenomegaly (150 mm) with homogeneous contours with multiple diffuse lymphadenopathyoccupying all cervical areas from 16 to 21 mm, axillary (23 mm) and right hilar (24 mm), presence of clusters of celiac-mesenteric, iliac, pelvic (right 26 mm and 30 mm on the left) and bilateral inguinal (27 mm) lymphadenopathies. In addition, the immunological workup performed on the patient was unremarkable (direct and indirect Coombs tests negative). At the end of this evaluation, our patient was prognostically staged for both her CLL and DLBCL (see Table I).

Therapeutic and evolutionary management

Our patient received 6 cycles of the R-EPOCH protocol (Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin). This protocol was administered at 21-day intervals (D1=D21) between 2 cycles. Mid-course and end-of-course evaluation workups allowed classification of our patient in complete remission (see Table II).

Table 1: General Information on the Patient (Diagnostic, Prognostic and Therapeutic Data)

Table 2: Variation of Biological Parameters Before and at End of Evaluation

M = months 

In chronic lymphocytic leukemia, the peak frequency occurs around 65 years of age and exceptionally before 40 years, with a median age at diagnosis around 70 years and a male predominance of the disease [4]. Previous studies suggest a median delay of Richter syndrome occurrence after chronic lymphocytic leukemia diagnosis of around two years, and in one- third of cases it is an untreated CLL [5-6]. Our observation does not reflect the literature data in that the age of CLL appearance in our patient was less than 50 years and the rapid evolution delay from the beginning of clinical manifestations to Richter syndrome (less than 6 months). Several symptoms were suggestive of Richter syndrome in our patient, including: the presence of B symptoms, rapid increase in lymph node volume in several involved territories, and a very high level of lactate dehydrogenase (LDH). This same finding was reported by Mao Z and collaborators. In addition to suggestive clinical-biological symptoms, PET with 18F-FDG could play a crucial role in the diagnostic accuracy of Richter syndrome. It has a sensitivity and specificity of more than 90% for the diagnosis of Richter syndrome and allows targeting the biopsy site [7]. This imaging technique is to this day not accessible in many countries and universities hospital centers in Africa, justifying most of the time practitioners ' request for an immunohistochemistry study on a lymph node. Apart from these characteristics, there were other prognosis factors in our patient that are described as being related to rapid occurrence of Richter syndrome in patients with CLL, among which We can cite: to lymphocytosis doubling time <3>

A simultaneous diagnosis of Richter syndrome and chronic lymphocytic leukemia is a rare finding that may be associated with inhibition of an anti- apoptotic gene (BCL2). It should be sought in the presence of pronounced symptomatology during CLL regardless of the patient's age. The diagnostic accuracy of Richter syndrome is provided by immunohistochemistry study, and therapeutic choice must take into account the existence of complex genetic aberrations.

Acknowledgments

To the medical staff of the various clinical hematology departments

Conflict of interest

None

Funding

None 

Author contributions

The manuscript was written by: Kouakou Boidy, Danho N. Clotaire and Keita Maxime

Kamara Ismaël, Silue A. Dohoma, Attiméré Yao Nicaise, Djeket Ruth, Doukouré Aboubacar, Bathily Moussa: participated in patient care as well as scientific writing.

Tolo A. Diebkilé and Koffi K Gustave (full professors of clinical hematology) participated in scientific supervision and manuscript correction.