Impact of Immunophenotype on Clinical Disease Characteristics and Outcomes in T-Cell Prolymphocytic Leukemia
Authors: Poh Christina , Chen Xueyan , Voutsinas Jenna M. , Warren Edus H. , Shadman Mazyar , Lynch Ryan C. , Till Brian G. , Ujjani Chaitra S. , Di Mengyang , Raghunathan Vikram , Smith Stephen D. , Wu Qian Vicky , Cherian Sindhu , Gopal Ajay K. 
Published: December 2024

Introduction
T-cell prolymphocytic leukemia (T-PLL) is a clinically aggressive malignancy of post-thymic T-cell origin. Given its rarity, there is a knowledge gap regarding the association of immunophenotype, cytogenetics, and clinical disease characteristics and outcomes.
Methods
We identified and collected clinical, immunophenotypic and cytogenetic data of patients with a diagnosis of T-PLL who were seen at the University of Washington/Fred Hutchinson Cancer Center between 2010 and 2024. Univariate logistic, linear and Cox regression were used to assess the association of pathologic features of interest with presenting clinical characteristics, time from diagnosis to initial treatment and survival outcomes, respectively.
Results
Fifty-five T-PLL patients were identified. Males comprised 51% of patients. Median age was 65 (range 39-89) years. The majority of patients (82%) were non-Hispanic whites, with African Americans, Asians/Pacific Islanders and Hispanics/Latinos contributing 11%, 5.5% and 1.8%, respectively. Ten (18%), 25 (45%) and 28 (51%) patients presented with hepatomegaly, splenomegaly and lymphadenopathy, respectively. Sixteen (29%) and 8 (15%) patients had cutaneous involvement and serous effusions, respectively. Six (11%) patients had secondary CNS involvement. Anemia and thrombocytopenia were noted in 18 (33%) and 27 (49%) patients, respectively. Median time from diagnosis to initiation of treatment was 42 (range 2-1,294) days. Forty-four (80%) patients received an alemtuzumab-containing treatment regimen, 39 (71%) as first-line therapy. Twelve (22%) patients underwent consolidative hematopoietic stem cell transplant. Thirty-three (60%) patients had a complex karyotype (≥3 aberrations). Abnormalities in chromosome 8, 11 and 14 were observed in 31 (56%), 19 (35%) and 30 (55%) patients, respectively. Thirty-eight (69%) patients had a TCL1 gene rearrangement. Nine (16%) patients lacked surface CD3 expression on either all cells or a major subset (sCD3-). About half (53%) of the patients had CD4+/CD8- phenotype, while CD4+/CD8+, CD4-/CD8+ and CD4-/CD8- phenotype were seen in 31%, 13% and 3.6%, respectively. Six (11%) patients had multiple phenotypic subsets and 4 (7%) underwent phenotypic switch throughout their disease course. sCD3- showed significantly decreased odds of having a complex karyotype when compared to sCD3+ (OR 0.21, 95% CI 0.04-0.92, p 0.05). Absence of CD4 expression on all or a major subset of abnormal cells (CD4-) showed significantly increased odds of having multiple phenotypic subsets as compared to cases with CD4 expression on all or a major subset (CD4+; OR 20.5, 95% CI 3.08-189, p 0.003). CD4-/CD8+ phenotype positively correlated with having multiple phenotypic subsets compared to CD4+/CD8- phenotype (OR 20.3, 95% CI 2.06-473, p 0.02) while CD4-/CD8- and CD4+/CD8+ phenotype did not. CD4- was associated with anemia at diagnosis (OR 5.67, 95% CI 1.29-30.4, p 0.03) and trended towards a shorter duration from diagnosis to initial treatment (Coef -0.57, 95% CI -1.10 to 0, p 0.06) compared to CD4+. Presence of multiple phenotypic subsets positively correlated with a shorter duration from diagnosis to initial treatment (Coef -0.82, 95% CI -1.50 to -0.19, p 0.02). Complex karyotype, CD4-, presence of multiple phenotypic subsets and phenotypic switch were not associated with hepatosplenomegaly, lymphadenopathy, cutaneous involvement, serous effusion, thrombocytopenia or CNS involvement at diagnosis. CD4- correlated with inferior progression-free survival (PFS; HR 2.72, 95% CI 1.20-6.18, p 0.02) and trended towards an inferior overall survival (OS; HR 2.50, 95% CI 0.99-6.35, p 0.05) compared to CD4+. CD4-/CD8+ phenotype was associated with inferior PFS compared to CD4+/CD8+ phenotype (HR 2.88, 95% CI 1.00-8.27 p 0.05). Presence of multiple phenotypic subsets correlated with inferior PFS (HR 2.97, 95% CI 1.20-7.37, p 0.02) and OS (HR 3.55, 95% CI 1.29-9.73, p 0.02). Complex karyotype, abnormalities on chromosomes 8, 11 or 14, TCL gene rearrangement, sCD3 or phenotypic switch were not associated with complete response to alemtuzumab therapy, PFS or OS.
Conclusions
In T-PLL, CD4- had inferior PFS compared to CD4+. Patients with multiple phenotypic subsets had inferior PFS and OS compared to patients without multiple phenotypic subsets. CD4- had 20.5 times the odds of having multiple phenotypic subsets when compared with CD4+.