1142 - Treatment of symptomatic paraneoplastic fluidothorax in CLL with novel agents: a single-center case series.

Introduction: Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in western world, presenting with various clinical manifestations. CLL cells are mainly present in the peripheral blood, bone marrow and lymph nodes. As a rare compartment involvement could be a pleural space. We describe here a case series of four patients (P1-P4) with symptomatic CLL paraneoplastic fluidothorax, successfully treated by novel agents.
Patients and cases description:
P1. Woman, born in 1941, CIRS (Cumulative Illness Rating Scale): 8 (facial herpes zoster, residual paresis of ocular nerves, dyslipidemia, hypertension, osteoporosis). CLL was diagnosed in 2018 (in 77 years), stadium Binet B, Rai I., IGHV unmutated, del 6q. I.st line of treatment: 6 x RCD (rituximab, cyclophosphamide, dexamethasone) have been given from November 2019 to April 2020 due to symptomatic fluidothorax, evacuated several times with 60% CLL infiltration verificated by flow cytometry. Lymph nodes with a maximum to 1 cm was observed. Patient achieved partial remission (PR) and due to progression receiving 2nd line of therapy – reduced ibrutinib (140 mg/day) since July 2020. At this treatment, fluidothorax regressed completely. Last follow-up (FU) was May 2023 (progression free survival - PFS 34 months).
P2. Man, born in 1948, CIRS: 9 (ischemic cardiac disease, atrial fibrillation, hypertension, hyperuricemia). CLL was diagnosed in 2012 (in 64 years), del 11 q, IGHV mutated. I.st line, 6 x FCR (fludarabine, cyclophosphamide, rituximab) was given from November 2013 to April 2013 with achieved complete remission (CR). Patient relapsed at september 2016 and from February to August 2017 patient received 5 x FCR, with CR 2. 3 rd line of therapy R-idelalisib patient received since December 2018, with progression at November 2022 – massive fluidothorax with need of several evacuations. Fluid CLL infiltration and pleura infiltration (histology) was verified. Abdominal lymph nodes was up to 2 cm. Since December 2022, patient is receiving venetoclax and achieved CR of fluidothorax. Last FU April 2023 (PFS 5 months).
P3. Man, born in 1951, CIRS: 8 (diabetes mellitus, diabetic foot disease, lower extremity ischemic disease). CLL was diagnosed in march 2020 (in 69 years), IGHV unmutated, 46 XY. 1st line treatment (1 x RCD, 3 x R- bendamustine) patient received from August 2021 to November 2021 due to generalised lymphadenomegalia (LAM) with maximum in retroperitoneal space up to 42 mm, fluidothorax and B symptoms), immunochemotherapy (ICT) had to be stopped due to infectious complications and patient achieved PR. From September 2022. patient started ibrutinib in the cause of progressive LAM and fluidothorax (70% CLL infiltration). In January 2022, there was no fluidothorax at skiagram and no palpable LAM. In February 2023 patient progressed in abdominal LAM (PFS 5 months), diagnosis of Richter transformation was established and after 3 cycles of ICT patient died in April 2023 due to progression (PD).
P4. Man, born in 1969, CIRS: 2 (hypertension). CLL was diagnosed in March 2017 (in 48 years), IGHV unmutated, del 11 q, del 13 q. I.st line treatment was initiated at December 2017 due to cytopenia and LAM), after 3 cycles of RCD, it was continued with 2 cycles FCR to April 2018. Because of PD, treatment was switched from June 2018 to R-idelalisib. In February 2019, TP53 mutation was detected. Second line of therapy was successful until June 2022, when the patient progressed with massive lymphadenomegaly, bone lesions, cytopenia and symptomatic fluidothorax. After 1 cycle of RCD, with no effect. Then venetoclax was started at June 2022 and the patient achieved CR. Last FU April 2023 (PFS 10 months).
Results and

Conclusions: We present two patients where fluidothorax was observed at the time of diagnosis and two patients who developed fluidothorax after prior therapies. Fluidithoraxes were in two patients sensitive to ibrutinib and in two patients to venetoclax (refractory to idelalisib). Only one patient progressed during FU to Richter transformation. Two patients received ICT as a first line treatment and were refractory. In two patients, fluidithorax developed at idelalisib treatment. Although the number of patients presented is too small to conclude on the best treatment choice for CLL-related fluidothorax, it seems that BTK inhibitors and BCL2 inhibitors could be an effective choice.
Grant support: IGA_LF_2023_010, IGA_LF_2023_005, MH_CZ-DRO(FNOL,00098892)