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

Appleby, Niamh; Eyre, Toby A.; Cabes, Maite; Jackson, Aimee; Boucher, Rebecca H.; Yates, Francesca; Fox, Sonia; Rawstron, Andrew; Hillmen, Peter; Schuh, Anna

doi:10.1186/s12885-019-5717-y

Cited by 23 publications

(13 citation statements)

References 44 publications

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“…In 2019, Appleby and colleagues has started the STELLAR trial protocol (NCT03899337), a prospective phase II randomized study of R-CHOP alone or in combination with acalabrutinib in a large cohort of RS patients. Results from this trial will highlight the safety, feasibility, and clinical activity of the addition of acalabrutinib to standard R-CHOP for RS [100]. Recently, the novel BTK inhibitor DTRM-12 has been tested in combination with the mTOR inhibitor everolimus and pomalidomide in RS, exploring the potential synthetic lethality of this therapeutic setting (NCT04305444).…”

Section: Combination Strategiesmentioning

confidence: 99%

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

Iannello

Deaglio

Vaisitti

2022

Curr. Treat. Options in Oncol.

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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.

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Section: Combination Strategiesmentioning

confidence: 99%

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

Iannello

Deaglio

Vaisitti

2022

Curr. Treat. Options in Oncol.

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“…The novel BTKi acalabrutinib was tested in 25 patients with DLBCL-RT, 48% of them with prior ibrutinib treatment, and showed a median PFS of 2.1 months [85]. Acalabrutinib is currently tested in combination with six courses of R-CHOP followed by acalabrutinib maintenance in newly diagnosed RT [86]. Concerning BCL2i, venetoclax monotherapy was tested in seven patients with DLBCL-RT, and three of them (43%) achieved PR [87].…”

Section: Novel Cll Therapies For Rtmentioning

confidence: 99%

Richter Transformation in Chronic Lymphocytic Leukemia: Update in the Era of Novel Agents

Tadmor

Levy

2021

Cancers

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Richter transformation (RT) is a poorly understood complication of chronic lymphocytic leukemia (CLL) with a dismal prognosis. It is associated with a switch in histopathology and biology, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or less frequently to Hodgkin’s variant of Richter transformation (HVRT). It occurs in 2–10% of CLL patients, with an incidence rate of 0.5–1% per year, and may develop in treatment-naïve patients, although it is more common following therapy. In recent years, there has been a deeper understanding of the molecular pathogenesis of RT that involves the inactivation of the TP53 tumor suppressor gene in 50–60% of cases and the activation of aberrations of NOTCH1 and MYC pathways in about 30% of cases. Compared to the preceding CLL, 80% of cases with DLBCL-RT and 30% of HVRT harbor the same IGHV-D-J rearrangements, indicating a clonal evolution of the disease, while the remaining cases represent de novo lymphomas that are clonally unrelated. Despite advances in understanding the molecular variations and the pathogenesis of the disease, there is still no significant improvement in patient outcomes. However, if no clinical trials were designed for patients with RT in the past, now there many studies for these patients that incorporate new drugs and novel combinations that are being explored. In this review, we summarize the new information accumulated on RT with special emphasis on results involving the novel therapy tested for this entity, which represents an unmet clinical need.

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“…This result could be at least partially explained by the excess of toxicity reported in elderly patients [14]. Despite the lower than expected efficacy of ibrutinib in DLBCL, a phase II trial in Richter syndrome with acalabrutinib, a second-generation BTKi, is ongoing [15].…”

Section: Btk Inhibitorsmentioning

confidence: 99%