Long-Smoldering T-prolymphocytic Leukemia: A Case Report and a Review of the Literature.

T-prolymphocytic leukemia (T-PLL) is a rare malignancy of mature T-cells with distinct clinical, cytomorphological, and molecular genetic features. The disease typically presents at an advanced stage, with marked leukocytosis, B symptoms, hepatosplenomegaly, and bone marrow failure. It usually follows an aggressive course from presentation, and the prognosis is often considered dismal; the median overall survival is less than one year with conventional chemotherapy. This case report describes a patient with T-PLL who, after an unusually protracted inactive phase, ultimately progressed to a highly invasive, organ-involving disease. After initial treatments failed, a novel treatment approach resulted in a significant response.

Clinical efficacy of immunochemotherapy with fludarabine, epirubicin and rituximab in the treatment for chronic lymphocytic leukaemia and prolymphocytic leukaemia.

Despite some considerable progress in the therapy for chronic lymphocytic leukaemia (CLL) owing to fludarabine-based regimens and rituximab, no curative treatment is available so far. We conducted an explorative phase II study in patients with CLL, prolymphocytic leukaemia (PLL) and leukaemic lymphoplasmacytic lymphoma (LL) with the combination of fludarabine, epirubicin and rituximab (FER) to improve the complete remission (CR) rate and progression-free survival (PFS). Fludarabine 25 mg/m(2) was administered i.v. on days 1-5 and epirubicin 25 mg/m(2) i.v. on days 4 and 5, and rituximab was added at a dose of 375 mg/m(2) i.v. day 1 in the first cycle and at a dose of 500 mg/m(2) in all consecutive cycles. Patients exhibiting responsive disease after FER were eligible to receive maintenance therapy of up to 12 cycles of rituximab 375 mg/m(2) bimonthly. Forty-four patients (38 CLL, 4 PLL and 2 LL) with a median age of 65 yrs (43-84 yrs) were evaluable. Seventeen patients with CLL had stage Binet C, 14 Binet B and seven symptomatic or rapid progressive stage Binet A. Cytogenetic features showed normal karyotype in nine cases, an isolated deletion (del) 13q in 12 patients, trisomy 12 in 7, del 11 in two and del 17p in 4. Half of the patients (48%) had mutated IgVH genes. Treatment with FER achieved an overall response rate of 95%, including 63% CRs and 32% PRs. Haematological toxicity was considerable. After a median follow-up period of 34 months (range: 8-84 months), median PFS was 61 months and overall survival was yet not reached. All patients with PLL and LL achieved CR. The data support the high efficacy of the combination of rituximab with chemotherapy (FE) and are suggestive of possible benefit with rituximab maintenance therapy for PFS and DFS.

Allogeneic hematopoietic cell transplant for prolymphocytic leukemia.

The poor prognosis of patients with prolymphocytic leukemia (PLL) has led some clinicians to recommend allogeneic hematopoietic cell transplant (HCT). However, the data to support this approach is limited to case-reports and small case series. We reviewed the database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to determine outcomes after allotransplant for patients with PLL. We identified 47 patients with a median age of 54 years (range: 30-75 years). With a median follow-up of 13 months, progression-free survival (PFS) was 33% (95% confidence interval [CI] 20%-47%) at 1 year. The most common cause of death was relapse or progression in 49%. The cumulative incidence of treatment-related mortality (TRM) at 1-year posttransplant was 28%. The small patient population prohibited prognostic factor analysis, but these data support consideration of allotransplant for PLL. Further study of a larger population of patients is needed to determine which patients are more likely to benefit.

Complex karyotype including chromosomal translocation (8;14) (q24;q32) in one case with B-cell prolymphocytic leukemia.

We report a case of a 64-year-old white female patient, who presented with symptomatic anemia (Hgb: 6.8g/dl), thrombocytopenia (platelets: 94,000/mcl) and leukocytosis (WBC: 156,000/mcl). Peripheral blood smear revealed markedly increased white blood cell count with predominance of atypical lymphoid cells of intermediate size, moderately dense chromatin, and prominent large single nucleoli. Bone marrow aspirate smear showed predominance (78%) of atypical lymphoid cells morphologically identical to those seen in the peripheral blood. The bone marrow core biopsy was hypercellular and packed with prominent infiltrate of prolymphocytes. Immunophenotypic analysis revealed a population of monoclonal cells (75% of all -erythroid cells) characterized by CD45+, CD19+, CD20+, CD5+, HLA-DR+, CD10-, CD23+/-, CD38+ and FMC7-. The abnormal cells were restricted to kappa light chain immunoglobulin with low intensity. Cytogenetic study showed an abnormal clone of eight cells with the following karyotype: 45,X,-X,add(8)(p11.2),t(8;14)(q24;q32),add(20)ql3[8]/46,XX[12]. The relative rarity of B-PLL and the heterogeneity of clinical and laboratory parameters make it difficult to define the natural history and prognosis in all cases. The optimal treatment for B-PLL is still unknown and to date there are no reports of chromosomal abnormalities as a prognostic factor. The patient was treated with six cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Complete remission was achieved according to the criteria defined by National Cancer Institute Working Group for CLL.

Typhlitis as a complication of alemtuzumab therapy.

Alemtuzumab is a humanized monoclonal antibody directed against lymphocytes through the CD-52 receptor, an antigen being found on > 95% of peripheral blood lymphocytes and monocytes, and to a smaller extent on granulocytes. It is an effective immunotherapeutic agent in patients with malignancies such as non-Hodgkin lymphoma, B cell chronic lymphocytic leukemia and T cell pro- lymphocytic leukemia. Adverse side effects are increasingly recognized in patients receiving alemtuzumab, mainly including fever, rigors, nausea/vomiting, skin rash; other severe alemtuzumab-related reactions have also been described, such as lymphopenia and neutropenia leading to both opportunistic (e.g. cytomegalovirus) and non-opportunistic infections. Digestive complications have more rarely been described, i.e.: gastroenteritis and peritonitis. We recently observed a case of particular interest as the patient with T cell prolymphocytic leukaemia treated with alemtuzumab, exhibited symptomatic reactivation of CMV infection and developed subsequently typhlitis.

Small cell variant of T-cell prolymphocytic leukemia with a gammadelta immunophenotype.

T-cell prolymphocytic leukemia (T-PLL) is a rare postthymic T-cell disorder. The disease is characterized by lymphadenopathy, splenomegaly, skin lesions, a high white blood cell count, and an aggressive clinical course. The small cell variant of T-PLL occurs in approximately 20% of patients. Most T-PLL patients express membrane T-cell receptors (TCR) of the alphabeta phenotype. The diagnosis of small cell variant T-PLL in a 56-year-old woman was based on the findings of abnormal lymphocytosis, immunophenotype, lymphadenopathy, and aggressive clinical behavior. Immunophenotype analysis showed that lymphocytes were positive for CD2, CD3, CD5, CD7, CD8, and TCR gammadelta antigens and negative for CD1a, CD4, and TCR alphabeta antigens. Southern blot analysis revealed rearrangement of the TCR Jgamma and Jdelta-1 genes. A cytogenetic study of peripheral blood showed a normal karyotype. T-PLL with a TCR gammadelta phenotype is very rare. This case was typical T-PLL except for the morphologically small cell type and the lack of the typical chromosome aberration. If cases accumulate in the future, the specific features of the gamma8 type of T-PLL will become clearer.

[Allogeneic bone marrow transplantation for chemotherapy-resistant T-prolymphocytic leukemia].

A 34-year-old female was referred to our hospital for the evaluation of atypical lymphocytosis. Leukocyte count at diagnosis was 17,900/microl with 58% atypical lymphocytes having a convoluted nucleus and prominent nucleoli. Because the leukocyte count increased to 43,600/microl, the patient was treated with 2'deoxycoformycin followed by CHOP combination chemotherapy. However, both treatments failed to achieve remission. We planned an allogeneic bone marrow transplantation from an HLA-matched unrelated donor. The patient was treated with Ara-C and etoposide before conditioning to decrease the high leukemia burden. After administration of total body irradiation (12 Gy in six fractions) and cyclophosphamide (total dose of 120 mg/kg) unmanipulated marrow cells were infused. Under prevention of GVHD by CsA and short-term MTX, leukocyte engraft was prompt at day 16, and acute GVHD grade II was observed. Because 9.4% of residual recipient type T-cells was seen with STR analysis on day 22, we decreased the dose of Cs'A. After the occurrence of mild acute GVHD, the residual T-cell number decreased. The patient is still in complete remission for up to 22 months after BMT. We conclude that allogeneic SCT is effective for the treatment of T-PLL.

Management of prolymphocytic leukemia.

B-cell (B-PLL) and T-cell (T-PLL) prolymphocytic leukemias are rare, poor-prognosis lymphoid neoplasms with similar presentation characterized by symptomatic splenomegaly and lymphocytosis. They can be distinguished from each other and from other T- and B-cell leukemias by careful evaluation of morphology, immunophenotyping, and molecular genetics. The clinical behavior is typically aggressive, although a subset of patients may have an indolent phase of variable length. First-line therapy for T-PLL is with intravenous alemtuzumab and for B-PLL is with combination purine analog-based chemo-immunotherapy. New B-cell receptor inhibitors, such as ibrutinib and idelalisib, may have a role in the management of B-PLL, especially for the patients harboring abnormalities of TP53. Allogenic stem cell transplantation should still be considered for eligible patients and may be the only current therapy capable of delivering a cure. In the past few years, many of the molecular mechanisms underlying disease pathogenesis and progression have been revealed and are likely to lead to the development of novel targeted approaches.

Fatal coronary artery disease after unrelated donor bone marrow transplantation.

Several factors are responsible for the occurrence of cardiac complications after bone marrow transplantation (BMT). These factors include the cardiotoxic effects of radiation therapy, antineoplastic and immunosuppressive drugs, abnormal immunologic reactions associated with graft-vs-host disease, and infectious agents. We report the case of a 45-year-old woman with T-cell prolymphocytic leukemia and no prior risk factors for coronary artery disease in whom sudden cardiac death occurred 2 1/2 years after allogeneic BMT from an unrelated male donor. Autopsy revealed severe 3-vessel coronary disease with grade 4/4 stenosis. This process was primarily nonatherosclerotic, with intimal hyperplasia of undetermined etiology. Furthermore, fluorescence in situ hybridization to identify the donor Y chromosome with simultaneous immunofluorescence labeling of smooth muscle actin suggested the presence of donor cells that transformed into myocytes. Coronary artery disease is an important, albeit rare, complication of BMT. Donor hematopoietic cells may contribute to its pathogenesis.

Treatment of T prolymphocytic leukemia with allogeneic bone marrow transplantation.

T prolymphocytic leukemia (T-PLL) is an unusual disease characterized by high white cell counts, older age at presentation, splenomegaly and a very aggressive clinical course. We describe a 47-year-old male with refractory T-PLL who was treated with high-dose chemoradiotherapy and allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling. The transplant was complicated by both acute and chronic graft-versus-host disease (GVHD). The patient achieved complete remission and remains in remission 3 years after the transplant.

Allogeneic peripheral blood stem cell transplantation with reduced intensity conditioning in primary refractory prolymphocytic leukemia: graft-versus-leukemia effect without graft-versus-host disease.

A patient with progressive prolymphocytic leukemia (PLL) received an allogeneic stem cell transplant using a reduced intensity conditioning regimen to avoid prohibitive toxicities. Early in the post-transplant period, a high donor-derived CD8+ count was observed. One year from transplantation, the patient was in complete remission, fully donor chimeric and with a normal performance status, suggesting that this approach may represent a useful treatment option in patients with refractory PLL.

Clinical and hematologic response of chronic lymphocytic and prolymphocytic leukemia persisting after allogeneic bone marrow transplantation with the onset of acute graft-versus-host disease: possible role of graft-versus-leukemia.

One patient with refractory B cell chronic lymphocytic leukemia (CLL) and another with refractory B cell prolymphocytic leukemia (PLL) underwent bone marrow transplantation (BMT) from HLA-identical siblings. Circulating malignant cells persisted at high levels in the patient with PLL and there was clinical evidence of disease progression soon after transplant in the patient with CLL. Starting 4-5 weeks post-BMT, cyclosporine was tapered rapidly to stimulate immunologic graft-versus-leukemia (GVL) reactions. There was a fall in the number of malignant cells and reversal of organomegaly with the onset of acute graft-versus-host disease (GVHD). Both patients received conventional doses of corticosteroids for GVHD which also may have contributed to disease response to some extent. Total clearance of the leukemic cells from the peripheral blood was seen in both patients, and clearance of the marrow was seen in the patient with CLL. However, both patients died of complications of severe GVHD. We conclude that GVHD may be associated with a GVL effect after allogeneic BMT for refractory chronic B cell lymphoproliferative diseases. Whether GVL reaction occur in the absence of clinically obvious GVHD after allogeneic BMT for CLL remains to be seen.

Cryptic deletion involving the ATM locus at 11q22.3 approximately q23.1 in B-cell chronic lymphocytic leukemia and related disorders.

B-cell chronic lymphocytic leukemia (B-CLL) follows a heterogeneous clinical course, and several biological parameters have been investigated to try to predict its clinical outcome. New staging systems including cytogenetics and CD38 expression as predictive values have been developed. Deletions of 11q22.3 approximately q23.1 detected at diagnosis in cases of CLL patients have been associated with a relatively aggressive disease. This region, which contains the ataxia telangiectasia mutated (ATM) locus, may be implicated in the pathogenesis of lymphoid malignancies. We developed a set of dual-color specific probes to evaluate the ATM deletion by means of fluorescence in situ hybridization (FISH). We also used flow cytometry to investigate CD38 expression. Forty-one patients with CLL or low-grade B-cell lymphomas were studied at diagnosis or before treatment. FISH showed that only three CLL patients had deletions in the 11q23 locus; all three had progressive disease and were resistant to treatment. These data show that our FISH set of probes efficiently detects ATM deletions in CLL. No correlation was found between ATM deletions and CD38 expression level. These results confirm the prognostic significance of ATM deletions in CLL.

Prolymphocytic leukemia.

PLL is an unusual clinical and morphologic variant of CLL which, in the more common B cell version, represents malignant transformation of a B lymphocyte at an intermediate stage of development. The immunophenotype of PLL cells, characterized by heavy cell surface staining for IgM and/or IgD and loss of mouse red blood cell receptors, suggests derivation from a slightly more mature cell than the one that gives rise to typical CLL. In patients with PLL prolymphocytic invasion accounts for massive splenomegaly and white counts of well over 100,000 per mm3 with minimal lymphadenopathy. Prolymphocytes are large cells with relatively open chromatin and prominent nucleoli. Extra material on the long arm of chromosome 14 is the most common cytogenetic abnormality. The clinical course of patients with PLL is aggressive, with median survivals usually of all stages. Combination chemotherapy regimens typically reserved for those with an unfavorable prognosis for non-Hodgkin's lymphomas probably are more effective in the treatment of patients with PLL than are the less myelosuppressive oral regimens used in CLL.

In vivo binding of mouse IgG via polyreactive surface IgM abrogates progressive lymphocytosis in prolymphocytic leukemia.

Surface IgM expressed by malignant CD5+ B-cells from patients with B-chronic lymphocytic leukemia (B-CLL) has previously been shown to bind mouse Ig in what appears to be an example of polyreactive antigen-binding activity. This report demonstrates the in vitro and in vivo binding of mouse Ig to the surface of malignant B-cells from a patient with B-cell prolymphocytic leukemia (B-PLL). In vitro studies showed that K121, a mouse monoclonal antibody, bound to the B-PLL cells via the same low-affinity binding interaction demonstrated to occur between mouse Ig and surface IgM expressed by B-CLL cells rather than in the conventional sense against a specific antigen via its antigen-binding site. With the view to using this phenomenon to target malignant B-cells, it was important to determine whether the low-affinity interaction also occurred in vivo. Infusions of K121 totalling 286 mg were administered to a B-PLL patient over 7 days. Binding of K121 to circulating B-PLL cells was demonstrable after the administration of 36 mg of antibody and was preceded by the appearance of free antibody in the serum. Throughout the period of the infusion, the rapid rise in the peripheral blood white cell count normally observed after leukopheresis was abrogated. However, the count rose markedly after cessation of the antibody infusion in parallel with a decrease in both free and cell-bound K121. There were no observable side effects and no host immune response to either species specific or idiotypic determinants on the mouse Ig was detected. The in vivo binding of mouse Ig together with the previous in vitro data suggest the potential for a novel targeting mechanism using a region of the mouse Ig molecule to target polyreactive Ig expressed by malignant cells in B-CLL and B-PLL.

B-cell prolymphocytic leukemia: a survey of 35 patients emphasizing heterogeneity, prognostic factors and evidence for a group with an indolent course.

We report a retrospective survey of 35 patients (18 males and 17 females) with B-Prolymphocytic leukemia (B-PLL) followed for a median of 63 months. Twelve patients fulfilled Galton's original clinical and hematological criteria, presented with prominent splenomegaly and hyperleukocytosis and showed rapid progression soon after diagnosis. Twelve cases with gradually increasing spleen size and prolymphocyte count had an indolent course. Seven of this group are alive 68 to 164 months after diagnosis, whereas five died from causes unrelated to PLL. Eleven patients who never developed impressive leukocytosis had a variable prognosis. In the group of 17 patients treated with chlorambucil and prednisone (CP) or cyclophosphamide, vincristine, prednisone (COP) 8 achieved a partial remission (PR) with a median response of 32 months. In the group of six cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) treated patients one achieved a complete remission and two PR (median response was maintained for 30 months). Three patients treated with 2CdA achieved good PR. Six patients remained untreated. Median survival was 65 months and the probability of overall survival for 3, 5, and 10 years was 63%, 56% and 35%, respectively. Anemia < 11 g/dl and lymphocytosis > 100 x 10(9)/l were predictors of shorter survival in this group of patients. Age over 70, gender, B-symptoms at presentation, spleen size, thrombocytopenia, low IgG and complement levels, presence of paraproteinemia and the pattern of bone marrow infiltrate were not significant. Our findings show that all B-PLL may not have such a poor prognosis as described in earlier reports. The existence of prior symptoms evolving gradually after years to obvious PLL and cases with mild prolymphocytosis could possibly lead to underdiagnosis of the entity. Identification and follow-up of such cases may suggest a different natural history, variable prognostic features and different survival curves for B-PLL patients. In the light of the above, we suggest that the therapeutic approach for B-PLL should always relate to the severity of the disease.

Improvement of quality of life after splenectomy in an HTLV-I carrier with T-cell prolymphocytic leukemia.

A 34-year-old woman of HTLV-I carrier with T-PLL, whose quality of life improved and survival was prolonged after splenectomy, is described. The patient had marked splenomegaly, generalized lymphadenopathy and marked proliferation of abnormal lymphocytes in the peripheral blood with an irregular nucleus, deeply basophilic cytoplasm and a single prominent nucleolus, which were positive for CD2, CD3, CD5, CD7, CD4 and CD8. Although the patient had serum antibody against HTLV-I, HTLV-I proviral DNA integration was not detected. She was diagnosed as an HTLV-I carrier with T-PLL and received combination chemotherapy and 15.1 Gy splenic irradiation. However, the generalized lymphadenopathy and splenomegaly did not improve. The patient underwent splenectomy to palliate abdominal distension and hypersplenism. After the operation, her symptoms improved dramatically and within a week her hemoglobin concentration and platelet count normalized. She was discharged from hospital two weeks after the splenectomy, however 11 months later, she relapsed and despite treatment with chemotherapy and alpha-interferon, she died two months after the second admission. Autopsy findings revealed that PLL cells had invaded the bone marrow, lymph nodes, liver, lungs, kidneys, uterus, ovaries and adrenal glands.

Management of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia in Western countries. The diagnosis requires mature-appearing lymphocytes in the peripheral blood to >5 x 10(9)/L. The immunophenotype typically includes B cell antigens CD19, CD20 and CD23, low expression of surface immunoglobulin and CD5+, with other T cell antigens absent. Bone marrow biopsy, although not required for diagnosis, must show at least 30% lymphocytes. Cytogenetic abnormalities are frequent in patients with CLL, and may be associated with poor prognosis. Clinically, most patients are asymptomatic at presentation, with incidental lymphadenopathy and/or hepatosplenomegaly in the routine physical examination. Infections by opportunistic pathogens are the major cause of death. Aggressive transformation occurs in 10% of patients with CLL, most commonly prolymphocytic leukaemia (PLL) and Richter's syndrome. PLL de novo must be differentiated from PLL of an aggressive transformation. The incidences of autoimmune diseases and solid or haemopoietic secondary malignancies are increased in patients with CLL. Clinical stage is the strongest prognostic factor in CLL. There is no indication for early intervention. The current recommendation to start treatment includes disease-related symptoms, massive and/or progressive hepatosplenomegaly or lymphadenopathy, increasing bone marrow failure, autoimmune disease, and recurrent infections. Alkylating agents (e.g. chlorambucil) and nucleoside analogues (e.g. fludarabine) are the most active agents for CLL. Fludarabine induces higher response rates, but no improvement in overall survival has been observed. Fludarabine is the drug of choice for the majority of patients with CLL. Chlorambucil may be helpful for elderly patients with poor performance, and for patients who do not tolerate fludarabine. No drug combination is better than single agents. For patients refractory to initial treatment, referral to a clinical trial is the best choice. Other salvage therapy includes retreatment with the same initial agent (chlorambucil or fludarabine) if initial response was observed, or fludarabine for patients refractory to chlorambucil. Promising new approaches include cycle-active agents, nelarabine, biological therapy such as anti-CD52 monoclonal antibody, bone marrow transplantation, including the use of submyeloablative preparative regimens ('minitransplant') to induce graft-versus-leukaemia effect, and gene therapy. Prophylactic antibacterials and intravenous immunoglobulin should not be used routinely during supportive care. Epoetin may be helpful for patients who have anaemia without obvious cause. Assessment of response to therapy in CLL has been updated by the National Cancer Institute Working Group, and these guidelines are used worldwide for clinical trials.

Prolymphocytic leukemia: diagnosis and treatment. A case report.

A patient with B-cell prolymphocytic leukemia (PLL) who has had a prolonged survival is presented. The patient was diagnosed incidentally while asymptomatic, but later developed progressive disease. He was refractory to alkylating agents and fludarabine, but responded to treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone. This patient's prolonged survival may be due partly to his diagnosis at an indolent phase, possibly representing the early phase of the natural course of the disease. Diagnosis, clinical course, and treatment options for PLL are discussed.

[Prolymphocytic leukemia: the therapeutic strategy]. / La leucemia prolinfocitica: strategia terapeutica.

Prolymphocytic leukemia (PLL) is a malignant lymphoproliferative disorder, characterized by massive splenomegaly, predominance of prolymphocytes in the peripheral blood and bone marrow, minimal lymph nodes enlargement and poor prognosis. It accounts for a 5-10% case of chronic lymphocytic leukemia (CLL). Patients age is usually over the fifth decade, the disease is 4.1 more common in males. More than 80% are B-lymphocytic derived cells showing a post-thymic phenotype. Median survival of B-PLL patients is 3 years, while only 7 months in T-PLL. Standard therapy of CLL with alkylating agents and prednisone have been not much effective in the treatment of PLL with a response rate of about 20%. Up to date no ideal treatment is available for PLL. A realistic goal is probably to achieve a clinical course transformation, from aggressive to mild, thus changing from short to long term prognosis. For this purpose the initial therapeutic approach cannot be limited to a single agent only. Splenic irradiation, intensive anthracyclines-based regimens, leukapheresis combine together represent the best therapeutic choice. Alkylating agents with or without prednisone may play a role in keeping indolent clinical course. Fludarabine has shown antileukemic activity against PPL even in patients resistant.