T-cell prolymphocytic leukemia (T-PLL)

Typical of the disease T-PLL is a predominance of the prolymphocytic cell population in three variants, which otherwise do not differ significantly clinically and immunophenotypically:

Cytomorphological assessment of peripheral blood is usually sufficient for diagnosis. In order to control the response, however, the examination of bone marrow aspirate and biopsy is necessary, since the definition of a complete remission (CR, complete remission) or a complete remission with incomplete marrow recovery (CRi, CR with incomplete marrow recovery) includes cytomorphological criteria. Thus, the percentage of T-PLL cells among bone marrow mononuclear cells must be less than 5% and bone marrow recovery must be measurable for evidence of CR (platelet count ≥100 x 10⁹ /L, hemoglobin ≥11.0 g/dL, neutrophils ≥1.5 x 10⁹ /L) (Staber et al. 2019).

T-PLL exhibits leukocytosis usually greater than 100 x 10⁹ /L and the cells express characteristic surface markers (Table 2).

T-cell lymphomas can be detected by immunophenotyping using an aberrant phenotype. For example, they show co-expression of the antigens CD4 and CD8. Loss or attenuated expression of certain T-cell-associated antigens such as CD5 or CD3 may also indicate T-cell lymphoma. The ratio of CD4- to CD8-positive T lymphocytes may be shifted, as may that of T cell receptor α/β to γ/δ.

In addition to cytomorphology, immunophenotyping is also mandatory for diagnosis. It can be used for clonality detection as well as for the detection of overexpression of the involved TCL1 oncogene (TCL1A/B or MTCP1) (Table 1). Based on the immunophenotype, the disease can also be differentiated from other T-cell diseases (Staber et al. 2019).

The most common chromosomal alterations in T-PLL involve chromosome 14. Inversion 14 (inv(14)(q11q32)) is observed in 80% of all patients (Matutes et al. 1996). 10% of cases have a reciprocal translocation between homologous chromosomes 14 (t(14;14)(q11;q32)) (Brito-Babapulle & Catovsky 1991). In both cases, there is a rearrangement of the T cell receptor alpha/delta (TRA/D) gene locus with the proto-oncogene TCL1 at the molecular level, resulting in increased expression of TCL1 (Pekarsky et al. 1999). Another fusion partner of TRA/D is the proto-oncogene MTCP1, which is homologous to TCL1 and localized on the X chromosome in band Xq28 (Stern et al. 1993). The t(X;14)(q28;q11) is also a typical aberration in T-PLL. In very rare cases, no rearrangement or corresponding overexpression of the TCL1 gene family is detectable despite fulfillment of the other diagnostic criteria for T-PLL (Table 1). These cases should be categorized as TCL1 gene family-negative T-PLL (Staber et al. 2019).

Aberrations of chromosome 8 are also observed in 70-80% of cases, which include i(8)(q10), idic(8)(p11), t(8;8)(p11~12;q12), and other unbalanced aberrations that cause trisomy 8q and thus overexpression of the MYC oncogene (Pekarsky et al. 1999, WHO 2022). In addition, 12p13 deletions, 13q deletions, and aberrations of chromosome 6 (33%) and chromosome 17 (26%) have been observed, the latter often leading to deletion of the TP53 gene (Soulier et al. 2001). 12p deletions cause haploinsufficiency of CDKN1B (Le Toriellec et al. 2008).

Complex karyotypes are detected in 70-80% of cases (WHO 2022). The number of cytogenetic aberrations correlates negatively with prognosis. A particularly unfavorable prognosis has been observed in patients with five or more aberrations (Hu et al. 2017).

By means of FISH analysis and molecular genetic studies, cytogenetically cryptic deletions on chromosome 11 in chromosome band 11q23 could be detected in the majority of patients. 11q23 deletions occur in approximately 57% of cases (Stengel et al. 2016). The ATM gene (ataxia telangiectasia mutated) is found on this gene locus, which is affected by genetic alterations due to deletions and/or mutations in over 70% of patients (Stilgenbauer et al. 1997, Stengel et al. 2016, Staber et al. 2019). Patients with ataxia teleangiectatica (congenital homozygous ATM mutation) are more likely than average to develop T-PLL (Brito-Babapulle & Catovsky 1991). Deletions of TP53 can also be detected in 26% of cases, mutations in 14% (Stengel et al. 2016).

Common molecular genetic mutations in T-PLL involve the JAK3 gene as well as the STAT5B gene in addition to the ATM gene, resulting in activation of the STAT5 signaling pathway (Kiel et al. 2014, Johansson et al. 2018, Schrader et al. 2018, WHO 2022). Mutations in the BCOR, JAK1, and TP53 genes also occur with lower incidence. For JAK3 mutations, a negative impact on patient survival has also been demonstrated (Stengel et al. 2016).