Treatment of T cell prolymphocytic leukemia

INTRODUCTION — T cell prolymphocytic leukemia (T-PLL) is a rare, clinically aggressive T cell neoplasm composed of lymphoid cells, typically with involvement of the peripheral blood, bone marrow, lymph nodes, and spleen. The name "prolymphocyte" is a misnomer, as the tumor cells in this disease are of post-thymic T cell origin. This class of neoplasms includes many cases previously classified as T cell chronic lymphocytic leukemia, a category no longer included in the current World Health Organization classification.

This topic will review the management of T-PLL. The diagnosis of T-PLL is presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia".)

INDICATIONS FOR TREATMENT — Not all patients with T-PLL require treatment at the time of diagnosis. Treatment is reserved for patients with symptomatic or "active" disease. This is principally because:

●With the possible exception of allogeneic hematopoietic cell transplantation, T-PLL cannot be cured by current treatment options.

●T-PLL is a heterogeneous disease. While T-PLL is usually a clinically aggressive disorder, up to 30 percent of patients with T-PLL present with initially stable or slowly progressive disease [1]. Early treatment of asymptomatic disease has not been shown to improve clinical outcomes.

Identifying "active disease" — We agree with guidelines from the T-PLL International Study Group (TPLL-ISG), which list the following disease-related complications as markers of "active disease" and indications for therapy [2]:

●Disease-related constitutional B symptoms. Significant fatigue (eg, Eastern Cooperative Oncology Group performance status ≥2 (table 1B)); unintentional weight loss (>10 percent body weight over ≤6 months); drenching night sweats and/or fevers, each without evidence of infection.

●Rapidly enlarging lymph nodes, spleen, and/or liver (eg, >50 percent increase in size over two months or diameter doubling over <6 months); or symptomatic enlargement of these organs due to T-PLL. In contrast, transient localized lymphadenopathy, occurring in response to localized infections, is not necessarily an indication for treatment.

●Bone marrow failure, manifesting as anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (platelet count <100 x 10⁹/L).

●Skin infiltration, pleural effusion, or central nervous system involvement.

●Rapidly increasing lymphocytosis. Threshold depends on baseline lymphocyte count and clinical picture. As an example, therapy may be appropriate for a patient with a baseline lymphocyte count over 30,000/microL with doubling of the lymphocyte count in <6 months, or an increase of more than 50 percent within two months.

Management of "inactive disease" — Among newly diagnosed patients with "inactive" T-PLL, we suggest observation rather than immediate treatment (algorithm 1). It is very important to monitor these patients closely because, unlike patients with chronic lymphocytic leukemia, patients with T-PLL inevitably progress, sometimes with a rapid course that may be fatal. (See 'Indications for treatment' above.)

During the observation period, we perform blood counts at monthly intervals along with a clinical examination. Of particular importance is the rate of increase in blood lymphocyte count and any evidence indicating emergence of progressive and/or symptomatic disease. A blood lymphocyte doubling time less than 8.5 months has been associated with a worse prognosis and may be considered evidence of disease progression [3]. Some clinicians choose to offer treatment in this setting, although it is our preference not to treat based on the doubling time alone. In addition to the doubling time, the initial level of blood lymphocyte count should be considered. For example, a doubling of the lymphocyte count from 10,000 to 20,000 per microliter in less than eight months in a patient who is free of symptoms does not have the same weight in deciding to initiate therapy as a rapid doubling of the lymphocyte count from 75,000 to 150,000 per microliter.

MANAGEMENT OF "ACTIVE DISEASE"

Pretreatment evaluation — Prior to the initiation of therapy for active disease, patients with T-PLL should undergo a pretreatment evaluation to determine the extent of disease, patient performance status (table 1A-B), and an assessment of comorbidities that are likely to have an impact on treatment options. Studies performed to confirm the diagnosis are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia", section on 'Evaluation'.)

In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with T-PLL:

●Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, beta-2 microglobulin, and lactate dehydrogenase (LDH).

●Serology testing for cytomegalovirus (CMV; IgM and IgG), herpes simplex virus (IgM and IgG), human immunodeficiency virus (HIV), hepatitis B (HBsAg and anti-HBc), and hepatitis C (anti-HCV).

●A computed tomography (CT) of the chest, abdomen, and pelvis to evaluate the bulk of disease and screen for unusual sites of involvement (eg, liver involvement). We prefer to use the International Working Group Response Evaluation Criteria in Lymphomas (RECIL) methodology to measure tumor burden based on the unidimensional measurements of three target lesions, rather than the more complicated Lugano criteria [2,4]. 18F fluorodeoxyglucose (FDG) positron emission tomography is not routinely used given the limited data regarding FDG avidity of T-PLL [2].

●Unilateral bone marrow aspirate and biopsy is performed in those with cytopenias. Samples should be sent for pathologic review, immunophenotyping, cytochemistry, and conventional cytogenetics.

●Individuals with childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. Treatment with alemtuzumab or purine analogs is unlikely to result in infertility. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Remission induction — Patients with active T-PLL progress quickly without treatment and have a median overall survival (OS) measured in months [5,6]. Therapy is offered with the goals of ameliorating symptoms and improving OS. While usually not curative, modern therapy with alemtuzumab will achieve a complete remission (CR) in the majority of patients, and a minority will experience long-term disease-free survival following transplantation.

Data regarding the treatment of T-PLL primarily come from retrospective analyses and small prospective trials. There have been no randomized trials in this population. Conventional alkylator or anthracycline-based therapies are largely ineffective. We and others prefer to use single-agent intravenous alemtuzumab for initial remission induction for most patients (algorithm 1) [2,7]. The purine analog pentostatin is added for patients who fail to attain a CR. Other experts may offer intravenous alemtuzumab in combination with pentostatin as initial therapy or treatment with fludarabine, mitoxantrone, and cyclophosphamide (FMC) followed by intravenous alemtuzumab in selected patients who may be less likely to respond to single-agent alemtuzumab (eg, with bulky disease, splenomegaly, and/or hepatic involvement) [7-11]. The published experience with other agents (eg, cladribine, fludarabine, nelarabine, and bendamustine) as single agents is limited to small series and case reports, largely in relapsed disease [12-15].

Our approach is largely consistent with the guidelines for the management of T-PLL from the T-PLL International Study Group [2] and the National Comprehensive Cancer Network [7], and for the management of mature T cell and NK cell neoplasms from the British Committee for Standards in Haematology [16].

Alemtuzumab — For most patients with active T-PLL, we recommend off-label use of the anti-CD52 antibody alemtuzumab (algorithm 1). Alemtuzumab is accessible through a distribution program from the manufacturer (Campath Access Program) [17]. The majority of T-PLL strongly express the CD52 antigen [18]. Very rarely, CD52 has been downregulated in relapsed cases, and this has been associated with a lack of response. Thus, tumor expression of CD52 should be confirmed before starting alemtuzumab therapy.

Retrospective and prospective studies of alemtuzumab-based chemotherapy have reported response rates ranging from 80 to 100 percent and 50 to 76 percent in patients with previously untreated and previously treated T-PLL, respectively. CRs are seen in 40 to 100 percent of patients [19-22]. In comparison, the overall response rate (ORR) with purine analogs is less than 50 percent, with few CRs and remission durations of less than one year [12,23-25]. While alemtuzumab has been considered the treatment of choice for T-PLL, responses are not durable, and additional strategies (eg, autologous or allogeneic hematopoietic cell transplantation [HCT]) should be considered for the consolidation of eligible patients. (See 'Post-remission therapy' below.)

Studies evaluating alemtuzumab in T-PLL have used different administration schedules, and the ideal schedule is unknown. Intravenous administration appears to be more effective than subcutaneous [19]. Infusion reactions are common with the first dose, so it is common to premedicate with acetaminophen and diphenhydramine and gradually increase the administered dose over a few days as tolerated until reaching the standard dose. We administer alemtuzumab 3 mg intravenously on day 1; 10 mg on day 2; and 30 mg on day 3, followed by 30 mg doses every Monday, Wednesday, and Friday beginning the following week [20]. The prevention and management of infusion reactions is discussed separately. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Alemtuzumab'.)

Alemtuzumab increases the vulnerability of patients to opportunistic infections, including fatal bacterial, viral, fungal, and protozoal infection, as well as reactivation of CMV, indicating that appropriate antibacterial and antiviral prophylaxis must be instituted when this agent is employed [25-34]. The most commonly reported prophylaxis regimens include antibiotics (eg, trimethoprim-sulfamethoxazole DS or cotrimoxazole) together with antiviral agents (eg, famciclovir) during therapy and until CD4+ cell counts are ≥200/microL, and for a minimum of two months after last treatment. CMV viremia should be measured by quantitative polymerase chain reaction (PCR) weekly during treatment. The approach to CMV management varies by center. Some use valganciclovir prophylaxis if viremia is present, while others use it only if the viral load is rising [34]. Our typical practice is to monitor patients as above. If a patient converts from CMV-negative to CMV-positive status or if a patient previously positive for CMV has an increase in viral load, we suspend therapy with alemtuzumab and begin treatment of CMV. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Alemtuzumab'.)

Less common but potentially life-threatening toxicities that have been reported in patients treated with alemtuzumab for chronic lymphocytic leukemia (CLL) include glomerulonephritis, hemophagocytic lymphohistiocytosis, autoimmune encephalitis, and stroke (ischemic and hemorrhagic) [35,36]. It is not clear whether these toxicities also occur in patients with T-PLL.

The following is a selection of the largest studies that have evaluated single-agent alemtuzumab in T-PLL:

●In a retrospective series of 76 patients, 72 of whom had failed at least one prior chemotherapeutic regimen, the ORR was 51 percent (40 percent complete) [20]. The median progression-free survival (PFS) and OS times were 4.5 and 7.5 months, respectively. Median OS was 15 months for patients achieving CR.

●A prospective study of intravenous alemtuzumab in 39 patients with previously treated T-PLL reported an ORR of 76 percent (60 percent complete) [21]. The median PFS and OS rates were 7 and 10 months, respectively. One patient remained in CR 10 years after allogeneic transplantation.

●In another study, 46 therapy-naïve patients with T-PLL, aged 36 to 85 years, were treated with single-agent intravenous alemtuzumab achieving an ORR of 92 percent with an 81 percent CR rate [19,22]. Two-thirds of patients were progression-free at a year and a third remained alive at four years. An additional nine patients who received alemtuzumab by the subcutaneous route had a markedly inferior response rate (33 percent) and this route of administration is therefore not recommended.

Small prospective studies have also evaluated the use of alemtuzumab in combination with other agents. As an example, in a multicenter phase II trial of 25 patients with T-PLL treated with fludarabine, mitoxantrone, and cyclophosphamide (FMC) followed by alemtuzumab reported that the ORR increased from 68 to 92 percent after the administration of alemtuzumab [8]. Median PFS and OS were 11.9 and 17.1 months, respectively. The combination of alemtuzumab plus pentostatin is discussed in the following section. (See 'Alemtuzumab plus pentostatin' below.)

Alemtuzumab plus pentostatin — Pentostatin is the purine analog that has demonstrated the greatest activity in T-PLL. Pentostatin has been evaluated in retrospective and small prospective trials both as a single agent and in combination with alemtuzumab [9,11,23]. Although the two drugs have not been directly compared in a randomized trial, single-agent pentostatin appears to have a lower response rate than single-agent alemtuzumab. For patients who have a suboptimal response to single-agent alemtuzumab, we suggest the addition of pentostatin (algorithm 1). This includes patients progressing at any time; those who have stable disease after 4 to 6 weeks; and those with a response less than CR after 10 to 12 weeks.

A phase II study evaluated the combination of alemtuzumab plus pentostatin in 24 patients with T cell leukemia or lymphoma, 13 with T-PLL [9]. The ORR in this subgroup was 69 percent (62 percent complete). For patients with T-PLL, the median OS and PFS were 10.2 and 7.8 months, respectively. Prophylactic antimicrobials with antiviral agents, antifungal agents, and anti-Pneumocystis jirovecii agents were mandatory during treatment and for a minimum of two months after the completion of treatment. Despite this, the most common toxicities were infection (75 percent), thrombocytopenia (37 percent), neutropenia (45 percent), and anemia (8 percent). CMV reactivation was seen in 38 percent of patients.

The addition of pentostatin to alemtuzumab increases toxicity, but it is unclear whether it increases the response rate since there have been no randomized trials comparing combination therapy with single-agent therapy. As such, we reserve the use of pentostatin for those with a suboptimal response to single-agent alemtuzumab. For such patients, we continue the alemtuzumab therapy three times a week and add pentostatin 4 mg/m² weekly. Patients who attain a CR with this approach can proceed to post-remission therapy. Patients with no improvement or progression after four to six weeks should be referred for clinical trials. (See 'Post-remission therapy' below and 'Clinical trials' below.)

Response evaluation — During remission induction, we see patients in clinic three times a week to assess treatment-related toxicity and disease-related symptoms. We have a more formal assessment at least every four to six weeks to assess response to therapy and toxicity; at a minimum, these visits include:

●An assessment of treatment-related toxicity and disease-related symptoms, including systemic B symptoms (fevers, chills, night sweats, fatigue, weight loss)

●A physical examination with particular attention to the lymph nodes, liver, and spleen

●Laboratory evaluation with a complete blood count with differential, serum chemistries, and serum lactate dehydrogenase

Once the peripheral blood lymphocyte count is <4000/microL, bone marrow function has recovered, and there are no signs of disease on physical examination, we assess for CR with CT of the chest, abdomen, and pelvis and a bone marrow aspirate and biopsy. If a hypocellular marrow is found, the bone marrow aspirate and biopsy should be repeated in four to six weeks.

Response criteria have been proposed by the T-PLL International Study Group (TPLL-ISG) [2]. Using these criteria, a CR requires all of the following:

●No systemic B symptoms attributable to T-PLL.

●No significant lymphadenopathy by physical examination; all previously enlarged lymph nodes should now have a long-axis diameter <1 cm.

●No hepatomegaly or splenomegaly (craniocaudal length <13 cm) by physical examination and by CT, and no involvement of other sites (eg, pleural or peritoneal effusions, skin infiltrates, central nervous system or other extramedullary sites).

●Absolute lymphocyte count <4000/microL (4 x 10⁹/L).

●Bone marrow with <5 percent of mononuclear cells with T-PLL phenotype. Testing for measurable residual disease (MRD, also called minimal residual disease) with more sensitive techniques is investigational; it is unclear whether low levels of MRD should impact the management of patients who achieve CR.

●Complete recovery of bone marrow function:

•Absolute neutrophil count ≥1500/microL (1.5 x 10⁹/L) (without growth factor)

•Untransfused platelet count ≥100,000/microL (100 x 10⁹/L)

•Untransfused hemoglobin concentration ≥11 g/dL (110 g/L) (without growth factor)

Patients who otherwise meet the criteria for CR but have persistent anemia, thrombocytopenia, or neutropenia that are thought to be due to treatment toxicity and not persistent T-PLL are classified as complete remission with incomplete marrow recovery (CRi).

Patients with T-PLL can develop an Epstein-Barr virus (EBV)-driven lymphoma (similar to post-transplant lymphoproliferative disease) after treatment with alemtuzumab. Transformation to an aggressive lymphoma may manifest as rapid progression of lymphadenopathy, infiltration of uncommon extranodal sites, systemic B symptoms, elevated serum lactate dehydrogenase, and/or hypercalcemia. A lymph node biopsy should be obtained if transformation into an aggressive lymphoma is suspected. (See "Histologic transformation of follicular lymphoma", section on 'When to suspect HT'.)

Post-remission therapy — Approximately 80 percent of patients with T-PLL who undergo initial treatment with alemtuzumab will attain a CR. However, without additional cytotoxic therapy, virtually all patients with T-PLL will relapse within one to two years. In contrast, patients who attain a CR and proceed with an allogeneic or autologous HCT may expect two- and five-year survival rates as high as 60 and 30 percent, respectively. For eligible patients who achieve a CR, we suggest consolidation with HCT rather than observation (algorithm 1). Other experts also offer HCT to patients who achieve a partial remission [7].

Allogeneic and autologous HCT appear to produce similar survival rates but differ in treatment-related mortality (TRM) and relapse rates. In general, we prefer allogeneic HCT for younger adults with a good performance status. The main challenges that remain are the relatively high TRM and relapse incidence, with less than half of transplanted patients in sustained remissions. Relapses usually occur early, within the first two years, although we have rarely seen a late relapse (more than five years). An autologous HCT may be considered for patients who achieve a CR but are not candidates for an allogeneic HCT because of age, fitness, or lack of a suitable donor.

●A multicenter retrospective study evaluated the outcomes of patients with T-PLL who underwent either autologous (16 patients) or allogeneic (23 patients) HCT following the attainment of a good partial response (three patients) or CR with alemtuzumab, and compared these patients with 26 patients with T-PLL who achieved a CR and survived at least six months after alemtuzumab treatment but did not proceed with HCT [22,37]. When compared with allogeneic HCT, autologous HCT had a lower TRM rate (6 versus 30 percent) but higher relapse rate (87 versus 39 percent) resulting in a median OS of 49 months for autologous versus 33 months for allogeneic HCT. When compared with the patients who did not receive HCT, those who received autologous or allogeneic HCT appeared to have a longer median OS (37 versus 20 months). Five-year OS for the autologous, allogeneic, and non-HCT groups was 37, 28, and 13 percent, respectively.

●Another retrospective analysis evaluated 47 patients with PLL (21 with T-PLL) who underwent allogeneic HCT in CR (36 percent), partial remission (18 percent), or with refractory disease (46 percent) [38]. With a median follow-up of 13 months, the cumulative incidence of TRM at one year was 28 percent and the one-year incidence of relapse or progression was 39 percent. The median PFS for the patients with T-PLL was 5.1 months.

●The European Group for Blood and Marrow Transplantation (EBMT) registry had 41 patients with T-PLL who had received an allogeneic HCT [39]. Survival at three years was only 21 percent with TRM and relapse rates of 41 percent. Almost half of the patients had refractory disease at the time of transplant, which adversely affected outcome and supports the argument for transplanting patients while they are in good remission.

●Another registry-based retrospective study included 27 patients with T-PLL who underwent allogeneic HCT in CR (14 patients), partial remission (10 patients), or in the setting of refractory disease (3 patients) [40]. With median follow-up of 33 months, 10 patients remain in continuous CR. Estimated rates of OS, PFS, and TRM at three years were 36, 26, and 31 percent, respectively. Approximately half (47 percent) relapsed with a median time to relapse of 11.7 months and all relapses occurring within the first two years.

As with all reports of new treatments, attention must be given to the possibility that patients receiving these treatments represent only a small, unrepresentative subset of patients with T-PLL. High intensity chemotherapy followed by allogeneic HCT in T-PLL has been limited by donor availability and the advanced age of most patients with this disorder. Following improvements in technique and supportive care and the introduction of reduced intensity conditioning regimens [41], the upper age limit for allogeneic HCT has been increased to 70 years. In addition, it seems likely that results with matched unrelated donor transplants are similar to those seen with matched sibling transplants, further extending the applicability of allogeneic HCT in T-PLL. (See "Donor selection for hematopoietic cell transplantation", section on 'Unrelated donors' and "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)

Patient follow-up — Following the completion of therapy, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depend upon the comfort of both the patient and physician and the type of post-remission therapy administered.

Once remission is confirmed, patients have an individually tailored follow-up every one to three months. Follow-up after transplant is discussed separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor".)

Relapsed disease usually presents with evidence of circulating tumor cells in the blood and/or skin changes. We have a low threshold to biopsy suspicious lesions found on imaging or physical examination. Relapse should be confirmed histologically before proceeding to salvage therapy. (See "Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia".)

Patients with T-PLL treated with alemtuzumab and/or HCT are immunocompromised and are therefore at risk for potentially lethal opportunistic infections with organisms such as Pneumocystis jirovecii (previously Pneumocystis carinii) and CMV. While prophylaxis for such infections is generally given, clinicians need to consider these organisms when patients become unwell. (See "Overview of infections following hematopoietic cell transplantation".)

TREATMENT OF RELAPSED PLL

Conventional therapies — There are limited options for the treatment of recurrent or refractory T-PLL and patients should be referred for enrollment in clinical trials. Median overall survival is six to nine months [2].

Repeat treatment with alemtuzumab may have activity in patients with T-PLL. A prospective study of alemtuzumab in 38 patients with relapsed or refractory T-PLL reported a second response in 5 of 12 patients treated with alemtuzumab at relapse [21]. However, some cases of T-PLL lose CD52 expression at the time of relapse resulting in resistance to alemtuzumab. As such, CD52 expression should be reassessed by immunophenotype prior to retreatment with alemtuzumab. There is some evidence that epigenetic therapies (eg, histone deacetylase inhibitors), with or without cladribine, may be able to modify CD52 and other molecules and thus overcome treatment resistance [42].

Nelarabine and bendamustine deliver response rates in the order of 30 to 50 percent, but response duration of only a few months. In a report of 15 patients with T-PLL treated with bendamustine, seven of whom had failed front-line therapy with alemtuzumab, the overall response rate was 53 percent (20 percent complete remission) with a median progression-free survival of five months and overall survival of 8.7 months [15]. Clinical outcomes were independent of prior exposure to alemtuzumab or other features.

The fact that there are some long-term survivors (>10 years) following reduced intensity conditioning allogeneic hematopoietic cell transplantation (HCT) suggests that this approach has curative potential, likely related to a graft-versus-leukemia effect. Allografted patients do still have a risk of relapse, and in our experience outcome after such relapse has been very poor. There is no clarity regarding the best relapse treatment in this setting or the benefit of donor lymphocyte infusion. There remains uncertainty about the optimal strategy for allogeneic HCT, which would be best addressed by conducting prospective clinical trials.

Targeted therapies — Preclinical data suggest that therapies targeting specific aberrant pathways (eg, STAT5, JAK3, MDM2, AKT) may be effective in T-PLL [43-47]. However, until there is stronger evidence for clinical benefit, targeted therapies should be given within the context of a clinical trial.

Given interpatient variation in molecular signature, several groups have adopted a "personalized" ex-vivo screen for active drugs in primary cell cultures. These screens have identified potentially active drugs and drug combinations. As described below, initial results suggest that targeted therapies can attain short remissions as single agents, but that rational combinations are likely to be required to achieve more durable remissions [48].

Clinical experience is limited to case studies or very small series, driven by the preclinical data showing in vitro activity. As examples:

●Venetoclax-based therapy – Single-agent venetoclax may result in transient responses [43,44,49]; remissions may be longer when venetoclax is used in combination therapy, although follow-up of all reports is relatively short. In one report of single agent venetoclax in two patients with multiply relapsed T-PLL, one patient discontinued therapy due to toxicity and the other achieved a response that lasted 131 days [43]. Although ibrutinib has modest activity as a single agent in T-PLL, it appears to prime cells to make them more sensitive to the effect of BCL-2 inhibition. Venetoclax plus ibrutinib was evaluated in two patients with multiply relapsed T-PLL; one discontinued therapy due to toxicity and the other had an ongoing response at one month [50]. This combination is being evaluated in the international phase 2 VIT-trial (NCT03873493). In another case study, the combination of venetoclax plus pentostatin provided a complete response of 10 months duration in a patient with refractory T-PLL [51].

●Tofacitinib-based therapy – Responses in T-PLL patients have been seen with the JAK3 inhibitor tofacitinib, alone [52] and in combination with ruxolitinib [53].

●Olaparib – The PARP inhibitor olaparib has also shown activity in T-PLL in a small phase 1 trial [54].

PROGNOSIS — T-PLL is a highly aggressive T cell leukemia. Patients with active T-PLL progress quickly without treatment and have a median overall survival measured in months [5,6]. While usually not curative, modern therapy with alemtuzumab will achieve a complete remission in the majority of patients, and a minority will experience long-term disease-free survival following transplantation. Median overall survival with modern therapy is one to three years [2]. A minority of cases has a more chronic course [1]. Such tumors typically express a memory T cell immunophenotype (CD45RO+/CD45RA-). Increased expression of TCL1 and the resultant increased activity of the serine-threonine kinase AKT appear to correlate with a worse outcome [3].

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

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●Beyond the Basics topics (see "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Assessing disease activity – T cell prolymphocytic leukemia (T-PLL) is a rare T cell neoplasm comprised of lymphoid cells, typically with involvement of the peripheral blood, bone marrow, and spleen.

Not all patients with T-PLL require treatment at the time of diagnosis. Treatment is indicated for patients with "active disease" manifest as disease-related constitutional B symptoms; rapidly enlarging lymph nodes, spleen, and/or liver; symptomatic bone marrow failure; extramedullary involvement; or rapidly increasing lymphocytosis (algorithm 1). (See 'Identifying "active disease"' above.)

●Close observation for "inactive disease" – Among patients with "inactive disease," we suggest close observation rather than immediate treatment (Grade 2C). Monthly blood counts are critical to monitor for progression. (See 'Management of "inactive disease"' above.)

●Remission induction for "active disease" – Patients with "active disease" require treatment (algorithm 1). A pretreatment evaluation helps to determine the extent of disease, patient performance status, and comorbidities that are likely to have an impact on treatment options. (See 'Pretreatment evaluation' above.)

Alemtuzumab-based therapy is the standard initial treatment for T-PLL. For most patients, we suggest initial treatment with single-agent intravenous alemtuzumab rather than with alemtuzumab-based combinations (Grade 2C). For patients who have a suboptimal response to single-agent alemtuzumab, we suggest the addition of pentostatin (Grade 2C). This includes patients progressing at any time; those who have stable disease after 4 to 6 weeks; and those with a response less than complete remission (CR) after 10 to 12 weeks. (See 'Remission induction' above and 'Response evaluation' above.)

●Consolidation with HCT – For eligible patients with T-PLL who achieve a CR, we suggest consolidation with hematopoietic cell transplantation (HCT) rather than observation (Grade 2C). Allogeneic and autologous HCT appear to produce similar survival rates but differ in treatment-related mortality and relapse rates. In general, we prefer allogeneic HCT for younger adults with a good performance status. An autologous HCT may be considered for patients who achieve a CR but are not candidates for an allogeneic HCT. (See 'Post-remission therapy' above.)

●Relapsed or refractory T-PLL – There are limited options for the treatment of recurrent or refractory T-PLL and patients should be referred for enrollment in clinical trials. (See 'Clinical trials' above and 'Treatment of relapsed PLL' above.)

●Prognosis – T-PLL is clinically aggressive. Patients with active T-PLL progress quickly without treatment and have a median overall survival measured in months. While usually not curative, modern therapy with alemtuzumab will achieve a CR in the majority of patients, and a minority will experience long-term disease-free survival following transplantation. Median overall survival with modern therapy is one to three years. (See 'Prognosis' above and 'Remission induction' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel Catovsky, MD, DSc (Med), FRCPath, FRCP, FMedSci, who contributed to earlier versions of this topic review.