T-PLL Presenting with an Indolent Course

T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell leukemia which usually presents with aggressive behavior. We report an asymptomatic T-PLL patient diagnosed by clinical features, lymphocyte morphology, and flow cytometry. Incidentally, she was found to have lymphocytosis and lymphadenopathy. Flow cytometry from blood revealed an abnormally increased CD4+ T-cell population. T-cell receptor clonality assessment by next-generation sequencing revealed a dominant clone in the ß-chain constant region. No pathogenic mutations in 25 lymphoma-related genes were found. Due to her asymptomatic T-PLL disease, we observed her clinical situation and blood count every three months for at least one year.


Introduction
T-cell prolymphocytic leukemia (T-PLL) is a rare, mature Tcell neoplasm, accounting for 2% of mature lymphoid leukemia cases in adults [1].Te 2022 World Health Organization classifcation categorizes T-PLL as mature T-cell leukemia originating from clonal small to medium-sized post-thymic T prolymphocytes [2].T-PLL was previously classifed as T-cell chronic lymphocytic leukemia (CLL) and treated following the criteria of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) [3].Te clinical course and pathogenesis of T-PLL, however, are much diferent from CLL. Te median age at diagnosis of T-PLL is approximately 65 years [1].A common presentation is leukocytosis (white blood cells >100 × 10 9 /L) with anemia and thrombocytopenia [1].Hepatosplenomegaly and generalized lymphadenopathy are also observed in patients with T-PLL [1].Te clinical course varies from asymptomatic disease to active disease.Asymptomatic T-PLL usually turns to a progressive symptomatic disease within 1-2 years [4].Herein, we report a patient diagnosed with asymptomatic T-PLL, which, based on her previous blood tests, remained stable for more than four years.

Case Presentation
A 78-year-old Tai female patient was admitted due to andrographolide-induced acute kidney injury (creatinine of 4.86 mg/dL from the baseline of 0.7 mg/dL) from Andrographis herbal supplement use.Her medical history included hypothyroidism from Hashimoto's thyroiditis, dietcontrolled dyslipidemia, and osteoarthritis of her right knee.Her complete blood count was 10.2 g/dL hemoglobin (Hb), 18.43 × 10 9 /L total white blood cells (WBC), which included an absolute lymphocyte count (ALC) at 14.38 × 10 9 /L, and normal platelet count (PLT) of 386 × 10 9 /L.She had a similar complete blood count documented four years prior (Hb at 11.4 g/dL, WBC at    dehydrogenase (LDH), uric acid, electrolytes, liver function test, blood urea nitrogen (BUN), and creatinine, were within normal limits.Her hepatitis B, hepatitis C, and human immunodefciency virus (HIV) profles were all negative.
For additional investigations, her peripheral blood smear showed increased small mature lymphocytes with cytoplasmic blebs, as shown in Figure 1.Flow cytometry from her blood revealed an increased lymphocyte gate population (64%).Te T-cell population (CD3+) accounted for 88% of total lymphocytes, while the B-cell population (CD20+) was detected in 12% of lymphocytes.Clonal B-cell could not be demonstrated by kappa or lambda restriction.A marked increase in the CD4+ T-cell population was shown with a CD4 : CD8 ratio of 84 : 5 (Figure 2).Bone marrow biopsy showed normocellular marrow containing 30-40 percent small to medium-sized atypical lymphoid cell proliferation.Immunohistochemistry revealed numerous CD3-positive cells with aberrant loss of CD7 (Figure 3).Combining the peripheral blood smear with the fow cytometry and bone marrow study, the results suggested a diagnosis of Tprolymphocytic leukemia.Her conventional chromosome analysis from bone marrow was normal (46, XX) for 20 metaphases.
DNA was extracted from her blood and then assessed for clonality using next-generation sequencing covering the Tcell receptor (TCR) beta chain constant region (Oncomine ™ TCR Beta-SR Assay, Termo Fisher Scientifc) [5] using a 25-gene panel (Termo Fisher Scientifc) for detection of somatic mutations.Both panels were performed on the IonTorrent S5.Te sequencing results revealed a dominant clone of TRBV6-5 (90.28%) (Figure 4).No pathogenic mutations were identifed among the 25 lymphoma-related genes.Te study was ethically approved by the Institutional Review Boards of Faculty of Medicine, Chulalongkorn University (IRB 776/66).
Due to her asymptomatic T-PLL, the treatment plan was to monitor her without intervention and follow up on her complete blood count and clinical features every three months.

Te latest 2022 World Health Organization classifcation of hematolymphoid tumors categorizes mature T-cell leukemia into four groups: T-prolymphocytic leukemia (T-PLL), T-large granular lymphocytic leukemia (T-LGLL), adult
T-cell leukemia/lymphoma (ATLL), and Sezary syndrome [2].Te characterization of these mature T-cell leukemias is summarized in Table 1 [6][7][8].T-PLL was previously classifed as T-CLL, but the clinical manifestations and pathogenesis of T-PLL and CLL are very diferent [9].T-cell prolymphocytic leukemia (T-PLL) is rare and occurs in about 2% of mature lymphoid leukemia cases in adults [1].T-PLL is rare in East Asia, accounting for less than 1% of T-cell lymphoma [10][11][12][13].In Tailand, from 2007 to 2020, there were no reports of T-PLL cases in our web-based registry system from 13 major Tai medical centers [14,15].To our knowledge, this report marks the frst documented case of T-PLL in Tailand in nearly two decades.
T-PLL diagnosis requires three major criteria or two major criteria with one minor criterion [6].Major criteria are >5 × 10 9 /L of T-PLL lymphocytes in peripheral blood or bone marrow, T-cell clonality, and abnormalities of 14q32 or Xq28 or expression of TCL1A/B or MTCP1.Minor criteria include abnormalities of chromosome 11 (11q22.3;ATM); abnormalities of chromosome 8 (idic(8), t(8; 8), trisomy 8q); abnormalities of chromosomes 5, 12, 13, and 22 or complex chromosome; and involvement of T-PLL specifc site (splenomegaly or efusion) [6].Tis patient fulflled two major criteria (number of T-PLL lymphocytes and T-cell clonality).However, diagnosis should also be based on the morphology and immunophenotype of the lymphocytes from peripheral lymphocytes.Bone marrow study is usually necessary only for the pre-and post-treatment evaluation [6].
For the indication for T-PLL treatment, only active disease should be treated, while asymptomatic T-PLL would be continuously observed.Criteria for active disease are constitutional symptoms (ECOG ≥ 2; unintentional weight loss of >10% in ≤6 months; drenching night sweats without infection; fever >38 °C without infection), bone marrow failure (hemoglobin <10 g/dL; platelet <100 × 10 9 /L); enlarging lymph nodes >50% in 2 months or diameter doubling in less than six months, symptomatic enlarged lymph nodes, spleen, or liver, increasing lymphocytosis (>30 × 10 9 /L; >50% in 2 months; lymphocyte doubling time less than six months), and extranodal involvement (organ infltration, peritoneal or pleural efusion, and central nervous system involvement) [17].If any of these criteria were observed, treatment should be initiated.Among treatment options, anti-CD52 alemtuzumab has shown the best overall response rate of more than 90% and progression-free survival between 8 and 11 months.Te recent recommendation for T-PLL is alemtuzumab induction treatment for 10-12 weeks in combination with allogeneic stem cell transplantation as consolidation therapy [17].T-PLL usually presents with aggressive disease (70%).Our patient was asymptomatic, which showed no indication to start treatment.

Conclusion
In summary, T-PLL is a rare, mature T-cell lymphoma, especially in East Asia.T-PLL may present with lymphocytosis mimicking asymptomatic chronic lymphocytic leukemia.An appropriate diagnostic approach and investigations are helpful for the diagnosis of T-PLL.

Figure 2 :
Figure 2: Flow cytometry from peripheral blood.(a) R represents lymphocyte gate and is further analyzed in (b)-(d).