CD5-positive lymphoproliferative disorders with atypical phenotypes are associated with inferior overall survival compared to typical-phenotype chronic lymphocytic leukaemia when treated with targeted agents. Free

Patients with a CD5-positive (CD5+) lymphoproliferative disorder (LPD) who have disease that is phenotypically atypical for Chronic Lymphocytic Leukaemia (CLL) but does not meet the diagnostic criteria for mantle cell lymphoma or other B-LPD are often treated as CLL. Several Phase 3 clinical trials have shown that targeted therapies (TT), specifically Bruton tyrosine kinase inhibitors (BTKi) and BCL-2 inhibitors (BCL-2i), significantly improve progression-free survival (PFS) compared to chemoimmunotherapy (CIT) for patients with CLL. It is not clear whether patients with atypical phenotype have the same outcome as patients with typical CLL.

The study aims to evaluate the clinical phenotype and overall survival (OS) in these patients and compare that with patients with typical CLL phenotype treated over a period of 12 years (January 2010 to December 2022). Data were abstracted from hospital records at a teaching hospital in Northern England, serving a population of approximately 800000. A patient cohort with CLL and CD5+ve LPD was identified through a search of the diagnostic laboratory database.

Out of a total of 124 patients diagnosed with CD5+ve LPD 30 (24%) patients required treatment, of which 4 patients were excluded from the analysis as they were subsequently treated elsewhere. During the same period 328 patients with CLL also required treatment from same institute.

Among the 26 treated patients, the median age at diagnosis was 78 (range (R) 44 - 88) years and 13 (50%) patients were male. Commonest presentation was incidental lymphocytosis in 9 (35%), other presentations were abdominal discomfort 3 (11.5%), B symptoms 3 (11.5%), lymphadenopathy 3 (11.5%), anaemia 3 (11.5%), infection 2 (8%) and others 3 (11.5%). At diagnosis B symptoms were present in 7 (27%), lymphadenopathy in 4 (15%) and splenomegaly in 12 (46%), median haemoglobin was 123 (R 61-151) g/L, WBC count was 12.9 (R 1.6-520) x10⁹/L, platelet count was 159 (R 52-428) x10⁹/L, LDH was 392 (R 114-1033) IU/L, and 7 (27%) patients had a paraprotein.

Prior to treatment 12 (46%) had B symptoms, 7 (27%) had lymphadenopathy and 15 (58%) had splenomegaly, median haemoglobin was 91(R 64-146) g/L, WBC was 13.5 (R 0.71-403) x10⁹/L, platelet count was105 (R 24-446) x10⁹/L and LDH was 368(106-2366) IU/L. Out of 25 patients who had imaging 18 (72%) had splenomegaly with median spleen size of 22 (R 13.5-34). Fluorescence in situ hybridisation (FISH) for CCND1/IGH rearrangement was performed in all but one patient, with all evaluated cases testing negative.

Chemotherapy (CT) or chemoimmunotherapy (CIT) was the first line treatment in 15 (58%) and targeted treatment (TT) in 11 (42%) including bendamustine + rituximab in 6 (23%), fludarabine + cyclophosphamide + rituximab in 3 (11.5%), dexamethasone+ cyclophosphamide+ rituximab in 2 (7.7%), chlorambucil in 3 (11.5%), rituximab alone in 1 (3.8%), acalabrutinib in 6 (23%), ibrutinib in 2 (7.7%), Zanubrutinib + venetoclax (clinical trial) in1 (3.8%) and venetoclax + obinutuzumab in 2 (7.7%). Clinical response to first line treatment included CR/Cri in 9 (34.6%), PR in 12 (46.1%), SD in1 (3.8%) and PD in 4 (15.4%). Radiological response was assessed in 15 (57.7%) patients of which CR seen in 8 (53%), PR in 5 (33.3%), SD in 1 (6.6%) and PD in 1 (6.6%). Five patients (19.2%) had subsequent line of treatment with median line of treatment 1 (R 1-6).

The median time from diagnosis to initiation of treatment was 5 (R 0–123) months for the whole group; 2 (R 0-55) months for CT/CIT group and 8 (R 0-123) months for the TT group. Median duration of follow up was 62 (95% CI 44.6-79.4) months for the whole group; 104 (95% CI 30.8-177.2) months for CT/CIT and 41 (95% CI 33.61-48.4) months for the TT group. Median OS for the whole CD5+LPD group was 75 (95% CI 45.4-104.5) months and that for 328 CLL patients treated over same period was 114 (95% CI 93.5-134.5) months (p=0.1). Median OS for the CD5+LPD patients treated with TT was not reached and for CLL patients was 100 (95% CI 65.3-134.6) months. 5 year estimated OS was 60% and 76% (p=0.04) respectively.

Treatment free survival at first line for the whole CD5+ve CLPD was 54 (95% CI 14.5-93.4) months; 64 (95% CI 30.9-97.1) for the CT/CIT group and not reached for the TT group (p=0.5).

Massive splenomegaly is a major feature in patients with CD5+LPD with atypical phenotype. These patients have an inferior OS outcome when treated with TT compared to CLL patients with typical phenotype.