In this issue of Blood, Staber et al report the initial activities of the newly created T-cell prolymphocytic leukemia (T-PLL) International Study Group (TPLL-ISG), which established consensus criteria for diagnosis, staging, and treatment response assessment of T-PLL.1 

T-PLL was recognized by the 2016 World Health Organization classification as a mature T-cell neoplasm characterized by proliferation of small- to medium-size T lymphocytes,2  which exhibit a mature immunophenotype (they are postthymic T cells) irrespective of their immature morphology (ie, nuclei with prominent nucleoli). The disease is characterized by a very aggressive course with progressive hyperlymphocytosis (>100 × 109/L), splenomegaly, hepatomegaly, and nodal and possibly extranodal (skin or pleural/peritoneal effusion, more rarely neurologic) involvement, often associated with B-symptoms.3  Thus, considering just the clinical course, T-PLL is quite different from chronic lymphocytic leukemia (CLL), but so far, diagnostic and staging criteria and response categories have been borrowed from CLL, eventually jeopardizing the interpretation of results from different studies. Considering the unique disease course of T-PLL and its dismal prognosis, disease-specific criteria are essential for better depicting the course of the disease, looking for prognostic factors, and defining clinically meaningful end points that will help assess the possible impact of different treatment options.

In the article by Staber et al, the panel of experts who participated in the TPLL-ISG proposed a systematic approach to T-PLL and developed disease-specific criteria for initial diagnosis and subsequent staging of T-PLL as well as for response to the limited available treatments. The PTLL-ISG introduced 3 major diagnostic criteria: (1) lymphocytosis >5 × 109/L, with typical prolymphocytes that harbored an aberrant immunophenotype; (2) clonality of the aberrant T lymphocytes, documented by either flow cytometry or molecular methods; and (3) typical genetic lesions (ie, TCL1A, TCL1B, or MTCP1 alterations or chromosome 14 abnormalities). The diagnosis of T-PLL is established if all 3 major criteria are met. As an alternative, if the first 2 criteria (which are the hallmark of the disease) associated with 1 minor genetic (ie, less common gene lesions) or clinical (ie, specific site involvement) criterion are met, then a diagnosis of TCL1A-family negative T-PLL can be made. The TPLL-ISG acknowledges that T-PLL may exist in 2 different forms: an initial stable or slowly progressive form (which is now defined as “inactive T-PLL,” which is detectable in about 20% to 30% of patients) and the more common rapidly progressive “active T-PLL.” These 2 forms are really 2 different phases of the same disease; indeed, all patients eventually progress to active disease within a limited time period.

The TPLL-ISG provides objective criteria for defining disease activity based on direct demonstration of tumor growth (by increasing lymphocytosis or enlargement of nodal or extranodal disease sites) or its clinical consequences (eg, symptomatic bone marrow failure or disease-related constitutional symptoms). This distinction of inactive and active disease serves as a staging system for defining the indication for treatment in T-PLL, which is reserved for patients with active disease. Finally, the most valuable work of the TPLL-ISG was defining homogeneous response categories. In view of its aggressiveness, T-PLL was approached as an acute leukemia, and complete remissions (including complete remission with incomplete marrow recovery) were based on the clearance of aberrant lymphocytes from both peripheral blood and bone marrow, in addition to resolution of nodal and extranodal involvements (demonstrated by imaging techniques). Furthermore, considering the chronic course of the disease and the availability of continuous treatment strategies, the PTLL-ISG has also introduced the concepts of “disease control rate” and “disease control time.” Notably, response categories also acknowledge the assessment of minimal residual disease by high-sensitivity methods, even if its actual clinical meaning remains to be elucidated in future studies.

With this work, the TPLL-ISG made remarkable efforts to harmonize the clinical practice for T-PLL, but defining common criteria by itself will not improve the dismal outcome for patients with T-PLL. Indeed, irrespective of the initial response, disease eradication remains a major challenge, because even complete hematologic remissions with undetectable disease inevitably relapse, and patients eventually die as a result of refractory disease or treatment-related complications. Alemtuzumab remains the best treatment of T-PLL, but despite its excellent initial response (overall response and complete response rates >90% and >80%, respectively), progression-free survival remains poor.4  The only curative approach for T-PLL remains allogeneic hematopoietic stem cell transplantation (HSCT), but even in this setting, the benefit of HSCT is based on a few retrospective series5  and is not confirmed in all studies.6  In a recent prospective observational study from the European Society for Blood and Marrow Transplantation that enrolled 54 patients (62% in complete remission) who received a transplant between 2007 and 2012, the 4-year progression-free survival was 30%, confirming that HSCT may result in long-term disease control in a limited proportion of patients,7  likely because of a graft-versus-leukemia effect.8 

Novel treatment strategies for T-PLL are urgently needed; candidate agents in clinical development for T-PLL include anti-BCL2 (alone9  or in combination with ibrutinib [NCT03873493]), JAK/STAT pathway inhibitors (eg, combined tofacitinib and ruxolitinib,10  or itacitinib [NCT03989466]), and anti–histone deacetylase (eg, romidepsin [NCT02512497]). In this scenario, the availability of robust diagnostic criteria, well-established indications for treatment, and homogeneous responses represent essential tools for investigating these novel therapies. Furthermore, the systematic investigation of biological features associated with disease progression may lead to the identification of molecular targets for the development of novel therapeutic agents. Future investigations are needed to validate these criteria and to identify baseline characteristics and longitudinal indicators associated with better long-term outcomes. Hopefully, this will also lead to the identification of meaningful clinical end points that may help assess the possible impacts of novel treatments. Indeed, we need to understand whether complete remission is required for long-term survival, or if even partial remission could result in satisfactory progression-free survival, especially in the era of novel, continuously given, target therapies. In contrast, if complete remission is the initial treatment goal, we will need to understand the meaning of minimal residual disease and its role in driving therapeutic interventions for subsequent maintenance or consolidation treatments. Of course this work from the TPLL-ISG is not the end of the story, but rather a starting point that paves the way for future clinical investigations that will improve the treatment of patients with T-PLL.

Conflict-of-interest disclosure: The author declares no competing financial interests.

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