Progression of Chronic Lymphocytic Leukemia into Hodgkin Lymphoma during Ibrutinib treatment. Case Report

Abstract

Chronic  Lymphocytic Leukemia (CLL) is a B cell lymphoproliferative malignancy  in which lymphomatous transformation to Richter's Syndrome (RS) occurs in 5-15% of patients. It is associated with Diffuse Large B Cell Lymphoma (DLBCL) in 80% of cases, while transformation to Hodgkin Lymphoma (HL) has been reported in  extremely rare cases with an estimated prevalence of 0.4%. Mutations in P53 and NOTCH1 genes are the most common aberrations observed in the progression to RS, and the cells may be clonally related or unrelated to the underlying clone. Bruton’s tyrosine Kinase (BtK) inhibitors, such as Ibrutinib (Ibru), has been approved for treatment of patients with 17p deletion, P53 mutations or relapsed / refractory CLL . However, it has been recently shown that BtK inhibitors can induce genomic instability in B cells, so in the context of the use of this new therapy, new emerging cases are of relevance.  In this work we aimed to report the clinical picture, pathology and genetics of a HL CLL transformation  after Ibru treatment .

Clinical case report: a 58-year-old man was diagnosed with LLC, by flow cytometry in April 2008 (Rai Stage II).  Among prognostic biomarkers,  IgHV was unmutated, ZAP70: 58% (+) and CD38: 80% (+). The patient was treated with Rituximab / Fludarabine / Cyclophosphamide and then as second line  of treatment, he received Bendamustine. He was followed up until June 2016, when he arrived at Hospital because of progressive disease. At that moment, the FISH analysis showed genetic alterations like: deletion 13q (34.5%), deletion 11q monoallelic: 3.1%, biallelic: 65.6%, normal TP53. The patient received Ibru 420 mg / day. After 35 days of therapy,  the blood count showed  a notable lymphocytosis  (WBC: 413 x 109 / l, 90.5% Lymphocytes,  absolute count: 176 x 109 / l), without clinical symptoms, marked decrease  size in  adenomegaly, and hepatosplenomegaly. Eighteen months later, the patient presented progressive constitutional symptoms,  with enlarging of supraclavicular lymphadenopathy, liver and spleen and pleural effusion. Supraclavicular lymph node biopsy  sugested small cell lymphocytic lymphoma with high grade transformation. Inmunohistochemistry confirmed the presence of Hodgkin Reed Sternberg cells (CD30+, CD15+) on a background of CLL cells. 

We reported a rare case of CLL with HL transformation  during treatment with Ibrutinib. Considering the increase in ITKB indications for this pathology, it is important to examine carefully  the new cases that arise in order to identify particular characteristics that suggest the causal mechanism.