T-Cell Prolymphocytic Leukemia
In 1973 Catovsky et al.1 were the first to describe a patient with prolymphocytic leukemia. T-cell prolymphocytic leukemia (T-PLL) is characterized by the proliferation of prolymphocytes with a mature postthymic phenotype (Fig. 1A).2 The median age at presentation is 63 years (range 33–91 years).3 Common presenting features of T-PLL include splenomegaly, generalized lymphadenopathy, skin infiltration, and serous effusions, particularly pleural.2, 3 The majority of patients present with widespread disease and an elevated lymphocyte count often over 100 × 109/L.4 Anemia and thrombocytopenia occur less frequently than in B-PLL.1 Human T-lymphotrophic viruses I and II (HTLV-I/II) are invariably negative by both serology and polymerase chain reaction (PCR) and a positive result for these viruses excludes this diagnosis.4–6
In the majority of patients there is a predominance of small- to medium-sized lymphoid cells with prominent nucleoli and a nongranular basophilic cytoplasm in the peripheral blood.2 The small cell variant of T-PLL occurs in approximately 20% of patients. In this form the cells are small, have condensed chromatin, and a small nucleolus.7 Another morphological variant of T-PLL, the cerebriform (or Sézary cell-like) variant, has also been described and accounts for 5% of patients.3, 7, 8
The mature T-PLL cells are by definition negative for terminal deoxynucleotidyl transferase (TdT) and CD1a and express the pan-T-cell markers CD2, CD5, and CD7.2, 3 CD7 expression is bright and CD3 expression can be absent or weak, suggesting that T-prolymphocytes may be at an intermediate stage of differentiation between thymic and postthymic T-cells.3, 9 The majority of patients (60%) have the CD4+, CD8− phenotype, with CD4+/CD8+ coexpression in 25%, and fewer cases (15%) having the CD4−/CD8+ immunophenotype.3 CD52 expression is commonly bright and TCR γ and β chains are clonally rearranged.3 A lower incidence of the memory T-cell pattern of CD45 expression (i.e., CD45RO+/CD45RA−) has been reported in the more indolent variety of T-PLL.10
T-PLL patients often have a complex karyotype with recurrent alterations including chromosomes 14, 11, and 8. Rearrangements of chromosome 14q32.1 through inversion [inv(14)(q11;q32)] and translocation [t(14;14)(q11;q32)] are the most common cytogenetic abnormalities reported in T-PLL (Fig. 2).11, 12 As a result of these rearrangements, TCL1, a gene that is physiologically expressed in CD4/CD8 double-negative thymocytes, is deregulated.13, 14 Typically, the TCL1 locus rearranges with the T-cell receptor (TCR) α/δ chain locus in the above mentioned rearrangements, but it can also rearrange with the TCR-β chain locus on chromosome 7 in another translocation [t(7;14)(q35;q32.1)].14–17 Furthermore, several patients with mature T-cell leukemias have the translocation [t(X;14)(q28;q11)], which results in the rearrangement of the MTCP1 gene (a member of the TCL1 gene family) located at Xq28.18, 19 Therefore, chromosomal rearrangements in T-PLL juxtapose TCL1 and MTCP1 to the TCR loci and lead to their activation. Recent genomic analyses of the 14q32.1 breakpoint region has revealed three additional genes, TCL1b, TNG1 (T-CL1 neighboring gene 1), and TNG2, which have an expression pattern similar to TCL1 in that they are not expressed in normal T-cells, but are expressed in T-PLL cell lines and cells from patients with T-PLL.20–22 Activation of TCL1 through hypomethylation of its promoter has also been described.23
The molecular events related to the above chromosomal aberrations are believed to be causal in the pathogenesis of T-PLL.24 The protein product of TCL1 (Tcl-1) can interact in vitro with Akt kinase, a component of the PI3-kinase signaling pathway, which is important in the survival and proliferative functions of T-cells.25, 26 Through this interaction, Tcl-1 may promote the nuclear translocation of Akt and enhance its kinase activity. The oncogenic effect of Akt is through phosphorylation and activation of prosurvival molecules such as raf, bad, and IKKα and Tcl-1 appears to further promote this activity (Fig. 3).25 Recently, another nuclear target for Akt has been described that appears to be important in the oncogenic effects of Tcl-1. Nuclear receptor Nur77 is an important transcription factor in T-cell receptor-mediated apoptosis in immature thymocytes undergoing selection.27 Akt can interact with Nur77 in a PI3K-dependent manner and inhibit the proapoptotic function of Nur-77.28, 29 This effect can be further accentuated through the interaction of Akt and Tcl-1 (Fig. 3).
Patients with the autosomal recessive disorder ataxia telangiectasia (AT) have biallelic inactivation of the ataxia telangiectasia mutated (ATM) gene. The association of AT with a clonal T-cell proliferation has been well described.30 Clonal cytogenetic abnormalities are present in the peripheral T-lymphocytes in 10% of patients with AT.31, 32 The abnormal lymphocytes in patients with AT share many features with the malignant cells in patients with T-PLL. Furthermore, in some patients with AT this clonal T-proliferation (known as AT clonal proliferation or ATCP) can progress into T-PLL, arguing that ATCP may represent the preleukemic stage of T-PLL.33 This is supported further by the observation that ATM-deficient knockout mice consistently develop an immature T-cell malignancy.34, 35 Furthermore, a subgroup of patients with T-PLL with an initial indolent course has been reported.10, 30, 33 Moreover, biallelic inactivation of the ATM gene at 11q23 has been demonstrated in sporadic T-PLL.36–38 This finding suggests that ATM aberrations can occur at a somatic level and play a role in malignant transformation of T-cells in patients with T-PLL.37
T-PLL is often resistant to conventional chemotherapy, with survival duration in the region of 7 months.4, 39 Nucleoside analogs such as deoxycoformycin (DCF) have been used with limited success. In an early study, 68 patients with postthymic mature T-cell malignancies including 31 patients with T-PLL were treated with DCF 4 mg/m2 weekly for the first 4 weeks, then every 2 weeks until maximal response.40 Toxicity was very low, with only one death from prolonged neutropenia. Forty-eight percent of patients with T-PLL responded, including 3 patients who achieved a CR and 12 patients a PR.40 More recently, Mercieca et al.41 updated their results of 145 patients treated using the above regimen, with the last 30 patients receiving weekly pentostatin until maximal response; an overall response rate of 32% was reported.
Dearden et al.42 treated 39 patients with T-PLL (including 2 previously untreated patients) with alemtuzumab and reported an overall response rate of 76%, with 60% CR and 16% PR. The median disease-free interval was 7 months (range 4–45 mos). Survival was significantly longer in patients achieving a CR, with 9 patients remaining alive up to 29 months after the completion of therapy.42 Seven patients underwent an autologous stem cell transplant after therapy with alemtuzumab, with three remaining alive and in CR up to 15 months after the transplant. Four patients had an allogeneic transplant and three remained alive in CR up to 20 months after the transplant.42 Although the majority of patients responded to alemtuzumab, all but two patients who were followed up for more than 1 year had relapsed at the time of reporting.
In a follow-up study, Dearden et al.43 administered a standard regimen of alemtuzumab to 11 previously untreated patients with T-PLL. All patients achieved a CR. Response duration was 2–25 months (median 10+ mos). After a median follow-up of 12 months (range 4–27 mos), 7 patients remained alive and 4 had undergone an autologous stem cell transplant. One patient died from sepsis in CR; 4 patients relapsed at 4–25 months (median 13 mos) and died from progressive disease. More recently, Keating et al.44 treated 66 patients (4 previously untreated) with alemtuzumab and reported a response rate of 51% (39.5% CR). The median duration of CR was 8.7 months (range, 0.13+ to 44.4 mos) and the median time to progression was 4.5 months (range 0.1–45.4 mos).44 The median overall survival was 7.5 months (14.8 mos for patients achieving CR). The most common adverse events were infusion reactions. Fifteen infectious episodes occurred in 10 patients. Activity of alemtuzumab in T-PLL may be superior to that seen in patients with CLL probably due to the higher expression of CD52 on normal and leukemic T-cells as compared with B-cells.45
Therefore, alemtuzumab is currently considered the treatment of choice in patients with T-PLL. However, in a significant proportion of patients the responses are not durable, and strategies to further prolong the time to progression and overall survival are needed. Combination of alemtuzumab with nucleoside analogs such as DCF is one such strategy, which should be investigated prospectively. Patients with an available donor should be considered for an allogeneic stem cell transplant using standard or nonmyeloablative regimens.