Novel Approaches for the Treatment of Patients with Richter’s Syndrome

Abstract

Opinion statementIn the last 10–15 years, the way to treat cancers has dramatically changed towards precision medicine approaches. These treatment options are mainly based on selective targeting against signaling pathways critical for or detrimentally activated in cancer cells in cancer cells, as well as exploiting molecules that are specifically expressed on neoplastic cells, also known as tumor-associated antigens. These considerations hold true also in the hematological field where a plethora of novel targeted agents have reached patients’ bedside, significantly improving clinical responses. Chronic lymphocytic leukemia (CLL) is an example of how targeted therapies, such as BTK, PI3K, or Bcl-2 inhibitors as well as anti-CD20 antibodies, have improved patients’ management, even when adopted as frontline treatment. However, these advancements do not apply to Richter’s syndrome (RS), the transformation of CLL into a very aggressive and fatal lymphoma, occurring in 2–10% of patients. RS is usually a fast-growing lymphoma of the diffuse large B cell or the Hodgkin’s variant, with a dismal prognosis. Despite advancements in depicting and understanding the genetic background of RS and its pathogenesis, no significant clinical results have been registered. In the last couple of years, several studies have started to investigate the impact of novel drugs or drug combinations and some of them have opened for clinical trials, currently in phase I or II, whose results will be soon available. This review will present an overview of current and most recent therapeutic options in RS, discussing also how results coming from xenograft models may help in designing and identifying novel treatment opportunities to overcome the lack of effective therapies.

Analisis Pasien Chronic Lymphocytic Leukemia Dan Diffuse Large B-Cell Lymphoma (Sindrom Richter)

“…Penting untuk membedakan diagnosis CLL-RS dengan DLBCL de novo berdasarkan pemeriksaan histologi dan imunohistokimia karena terkait dengan keputusan pemberian terapi. DLBCL de novo sebagian besar kemosensitif, sedangkan CLL yang berkembang menjadi RS memiliki karakterik kemoresisten dan luaran yang buruk dengan median overall survival sekitar 12 bulan (Andrea et al, 2022).…”

“…Rata-rata angka keberhasilan sekitar 8-10 bulan dengan agen kemoterapi (contohnya hyper-fractionated cyclophosphamide, vincristine, liposomal daunorubicine dan dexamethason (hyper-CVXD), cyclophosphamide, doxorubicine, vincristin dan prednisone (CHOP), mesna, ifosfamid, mioxantrone dan etoposide (MINE), fludarabine, cyclophosphamide dan rituximab (FCR) ataupun kombinasi etoposide, metilprednisolon, high dose cytarabine dan cisplatin (ESHAP) dengan ataupun tanpa Rituximab. Secara keseluruhan respon terapi lebih tinggi ketika Rituximab ditambahkan sebagai regimen terapi, walaupun tidak signifikan secara statistik, rata-rata survival dengan kemoterapi konvensional dengan atau tanpa Rituximab adalah kurang dari 12 bulan (Andrea et al, 2022;Mouhssine et al, 2022).…”

A molecular circuit linking the BCR to the NAD biosynthetic enzyme NAMPT is an actionable target in Richter syndrome

“… 14 In addition, it is important to explore new drugs or new combination strategies to achieve better and longer lasting responses. 15 Our laboratory has extensively worked on this topic, exploiting xenograft models derived from patients with RS (RS-PDX) that were established from 4 different patients with RS and that maintain a tight resemblance to the primary tumor. 16 We have analyzed the role of novel antibody drug conjugates targeting RS using tumor-specific antigens, such as ROR1, 17 or B-cell restricted targets, such as CD37.…”

Richter transformation in Chronic Lymphocytic Leukemia

“…Current therapeutic options for RS include chemo‐immunotherapy, cellular therapy, or experimental use of novel agents 5 . Anyways, RS therapy remains suboptimal and new trials are needed to increase its effectiveness and consequently improve patients' survival.…”