[Cerebriform variant type of T cell prolymphocytic leukemia: Report of one case]. / Leucemia prolinfocítica T variante de células cerebriformes: Presentación de un caso y revisión de la literatura.

T cell Prolymphocytic Leukemia (T-PLL) is a rare and aggressive mature T cell Lymphocyte Leukemia. Twenty five percent of cases present as a small cell variant, and only 5% as a cerebriform variant. We report a 58 year-old man with rapidly progressive severe leukocytosis, skin lesions, lymphadenopathy, hepatosplenomegaly and pleural effusion. The lymphocytes had a cerebriform type. The diagnosis of T-PLL variant was made by morphology and immunophenotype study of peripheral blood. Karyotype was found to be complex. He was refractory to chemotherapy and died two months later.

T-Cell Dynamics in Chronic Lymphocytic Leukemia under Different Treatment Modalities.

PURPOSE: Using next-generation sequencing (NGS), we recently documented T-cell oligoclonality in treatment-naïve chronic lymphocytic leukemia (CLL), with evidence indicating T-cell selection by restricted antigens. EXPERIMENTAL DESIGN: Here, we sought to comprehensively assess T-cell repertoire changes during treatment in relation to (i) treatment type [fludarabine-cyclophosphamide-rituximab (FCR) versus ibrutinib (IB) versus rituximab-idelalisib (R-ID)], and (ii) clinical response, by combining NGS immunoprofiling, flow cytometry, and functional bioassays. RESULTS: T-cell clonality significantly increased at (i) 3 months in the FCR and R-ID treatment groups, and (ii) over deepening clinical response in the R-ID group, with a similar trend detected in the IB group. Notably, in constrast to FCR that induced T-cell repertoire reconstitution, B-cell receptor signaling inhibitors (BcRi) preserved pretreatment clones. Extensive comparisons both within CLL as well as against T-cell receptor sequence databases showed little similarity with other entities, but instead revealed major clonotypes shared exclusively by patients with CLL, alluding to selection by conserved CLL-associated antigens. We then evaluated the functional effect of treatments on T cells and found that (i) R-ID upregulated the expression of activation markers in effector memory T cells, and (ii) both BcRi improved antitumor T-cell immune synapse formation, in marked contrast to FCR. CONCLUSIONS: Taken together, our NGS immunoprofiling data suggest that BcRi retain T-cell clones that may have developed against CLL-associated antigens. Phenotypic and immune synapse bioassays support a concurrent restoration of functionality, mostly evident for R-ID, arguably contributing to clinical response.

[Successful treatment of T-cell prolymphocytic leukemia (T-PLL) with fludarabine monophosphate].

We report a 79-year-old woman with T-cell prolymphocytic leukemia (T-PLL) who was successfully treated with fludarabine monophosphate. She was admitted to our hospital because of dyspnea on effort. On admission, anemia and hepatosplenomegaly were apparent but lymphadenopathy was absent. Peripheral blood examination showed anemia and leukocytosis with 29.5% abnormal lymphocytes. The bone marrow was infiltrated with 84.1% abnormal lymphocytes. The nucleolus was visible in some of these abnormal cells. These cells were positive for CD2, CD3, CD4, CD5, CD7, CD38, CD52, and negative for CD8, CD10, CD19, CD20, CD25, CD56. Based on these findings, she was diagnosed as having T-PLL. Therapy with oral cyclophosphamide (50 mg/day) was started, but was discontinued because of agranulocytosis. Then, she received intravenous fludarabine monophosphate (30 mg/day) on days 1-5 every four to five weeks. The reticulocyte count increased gradually, and she became free from red cell transfusions. Unfortunately, she finally died from massive gastro intestinal hemorrhage, but T-PLL was well controlled at the time of death.

Papuloerythroderma-like cutaneous involvement of a CD62L- subclone of T-cell prolymphocytic leukemia.

We report the case of an 88-year-old Japanese man with erythrodermic involvement of T-cell prolymphocytic leukemia (T-PLL). He had a history of pharyngeal diffuse large B-cell lymphoma successfully treated with polychemotherapy including cyclophosphamide and epirubicin, 6 years before the current illness. He presented with numerous reddish, coalescing, flat-topped papules on the trunk and extremities, sparing the skin folds of the abdomen, the features of which mimicked those of papuloerythroderma. Immunohistochemistry showed perivascular and epidermotropic infiltration of CD3+ CD4+ T cells in the cutaneous lesion. However, flow cytometric analysis revealed that the skin infiltrating T cells were negative for surface CD4, and that CD3+ CD4- CD8- cells made up 92% of the T-cell fraction of peripheral blood. The circulating atypical T cells had a round or oval nucleus and prominent nucleoli, and the deletion of chromosomes 6q, 13 and 17. These cytological profiles were consistent with those of T-PLL and distinct from those of Sézary cells. The same T-cell clone was detected in the cutaneous lesion and peripheral blood, but the expression of CD62L was absent in the skin infiltrates and present in the circulating cells. No specific mutation was detected in STAT3 or STAT5B. Although low-dose oral etoposide had a beneficial effect on the skin rash, a fatal crisis of marked leukocytosis (169 × 103 /µL) occurred 19 months after the illness onset. CD62L-leukemic cells of T-PLL may infiltrate the skin to form papuloerythroderma-like cutaneous lesions.

Concomitant T-cell prolymphocytic leukemia and visceral leishmaniasis: A case report.

RATIONALE: T-cell prolymphocytic leukaemia (T-PLL) is a rare aggressive lymphoid disease featured by a significant increased lymphocyte count and obvious hepatosplenomegaly with poor prognosis. The concomitant presentation of T-PLL and visceral leishmaniasis (VL) has not previously been reported. PATIENT CONCERNS: The patient initially suffered from anorexia, skin pigmentation, fever and hepatosplenomegaly. Bone marrow smear described leishmania and antibody test was positive. VL was diagnosed and he was given antimony gluconate therapy. His symptoms recurred. DIAGNOSIS: A combination of serological rk39 test, morphologic evaluation and immunophenotyping by flow cytometry finally supported the diagnosis of concomitant VL and T-PLL. OUTCOMES: Amphotericin B was used for the treatment of VL first and a referral for treating T-PLL after recovery from VL was suggested. Unfortunately, the patient requested to be discharged. Telephone follow-up indicated that he died a few days after leaving the hospital. LESSONS: Due to the rarity of the disease combination, the pathogenesis association of T-PLL and VL is unclear. However, a duly diagnosis is crucial for treatment. In immunosuppressed patients due to malignancies and treatment, VL should be considered as an opportunistic infection. In VL infections, the clinical manifestations mimicking hematological malignancies may cover up the underlying disease. Under such conditions, a complete work-up based on laboratory test is necessary to achieve a correct diagnosis.

Phenotypical heterogeneity of CD4+CD8+ double-positive chronic T lymphoid leukemia.

Chronic T lymphoid leukemias are defined as leukemias of post-thymic T cells. The CD4+CD8+ double-positive (DP) phenotype is seen in a few cases. Since DP generally occurs in thymic T cells, whether the DP T leukemia cells represent thymic or peripheral T cells has been a matter of controversy. To address this issue, we studied phenotypical features in eight cases of DP T cell leukemia. Thymic DP T cells and peripheral CD8+ T cells have CD8 of alphabeta subunit, while CD8alphaalpha is induced in CD4+ T cells on activation with IL-4. We found that two patients with DP T large granular lymphocyte leukemia (LGLL) showed dim expression of CD8alphaalpha, identical to the phenotype on IL-4-activated DP-T cells. The leukemic cells of these patients expressed IL-4 mRNA and produced high levels of IL-4. These findings suggest that they may be derived from peripheral CD4+ T cells. Three patients with adult T cell leukemia/lymphoma (ATLL) showed CD8alphaalpha, suggestive of an activated peripheral T cell origin. One case expressed CD8alphaalpha dim and IL-4 mRNA, while the other two cases expressed no IL-4 mRNA and showed CD8alphaalpha bright phenotype, features not found in normal T cell populations. Three patients with T-prolymphocytic leukemia (T-PLL) expressed CD8alphabeta. The DP phenotype is relatively common in T-PLL, and CD4+CD8alphabeta+ is characteristic of thymic T cells. The DP T-PLL cells did not express TdT,CD1 or recombination activating gene-1 (RAG-1), which is down-regulated at the late stage of thymic T cell development. On the basis of these findings, we propose a late thymic origin for DP T-PLL. The phenotype of DP T cells differed for each entity and appeared to correlate with minor normal DP T cell population.

Epigenetic therapy overcomes treatment resistance in T cell prolymphocytic leukemia.

T cell prolymphocytic leukemia (T-PLL) is a rare, mature T cell neoplasm with distinct features and an aggressive clinical course. Early relapse and short overall survival are commonplace. Use of the monoclonal anti-CD52 antibody alemtuzumab has improved the rate of complete remission and duration of response to more than 50% and between 6 and 12 months, respectively. Despite this advance, without an allogeneic transplant, resistant relapse is inevitable. We report seven complete and one partial remission in eight patients receiving alemtuzumab and cladribine with or without a histone deacetylase inhibitor. These data show that administration of epigenetic agents can overcome alemtuzumab resistance. We also report epigenetically induced expression of the surface receptor protein CD30 in T-PLL. Subsequent treatment with the anti-CD30 antibody-drug conjugate brentuximab vedotin overcame organ-specific (skin) resistance to alemtuzumab. Our findings demonstrate activity of combination epigenetic and immunotherapy in the incurable illness T-PLL, particularly in the setting of previous alemtuzumab therapy.

A patient of CD4-/CD8+ chronic T-cell leukemia associated with hypercalcemia.

A patient with chronic T-cell leukemia characterized by a suppressor phenotype is reported. A 71-year-old woman presented with symptoms and signs of hypercalcemia. Peripheral blood specimen showed abnormal lymphoid cells with an oval to cleaved nucleus, rather condensed chromatin, occasional prominent nucleolus, and basophilic cytoplasms with vacuoles which seems to be a T-cell counterpart of B-cell chronic lymphocytic leukemia with mixed cell types. The phenotype of these cells was CD4-, CD8+, CD5+, CD6+ with poor expression of CD3, CD7, and CD25. Southern blot analysis of T-cell receptor beta-chain gene revealed one allele rearranged band. The serum antibodies were positive against human T-cell leukemia virus, type I-associated antigens, but monoclonal integration of proviral DNA was not detected in the leukemic cells suggesting that she was just a carrier of this virus. Interestingly, serum PTH-related peptide (PRP) was elevated. The combination therapy with vincristine and prednisolone for leukemia decreased not only the number of leukemic cells but also the serum PRP levels. The clinical course was aggressive. She only responded transiently to treatments, and died of renal failure due to uncontrollable hypercalcemia six weeks after admission.

Lineage promiscuity in leukemia studies of T-cell receptor and immunoglobulin genes.

Using appropriate DNA probes, the configurations of the T-cell receptor beta-chain genes and immunoglobulin heavy-chain genes were studied in patients diagnosed as having the following malignancies: 7 chronic myeloid leukemia, 13 acute myeloblastic leukemia, 9 acute lymphocytic leukemia and 20 chronic lymphocytic leukemia. Rearrangements not corresponding to the immunotype were unexpectedly found in lineage neoplasias.

Enzyme activities of leukemic cells and biochemical changes induced by deoxycoformycin in vitro--lack of correlation with clinical response.

Deoxycoformycin (DCF) is a specific inhibitor of adenosine deaminase (ADA) and has been shown to be active in lymphoid neoplasms. Cytotoxicity is thought to be mediated by the accumulation of deoxyadenosine (AdR) and deoxyadenosine triphosphate (dATP) which inhibits ribonucleotide reductase and DNA synthesis in rapidly proliferating cells. Others suggested mechanisms leading to cell death particularly in non-dividing cells include depletion of ATP and NAD pools, inhibition of S-adenosylhomocysteine (SAH) hydrolase and induction of DNA strand breaks. In patients with high leukemic counts who were subsequently treated with DCF, we have studied (a) the levels of ADA, ecto-5'-nucleotidase (5NT), deoxyadenosine kinase (AdR-kinase) and SAH-hydrolase in the leukemic cells; [b) the in-vitro effects of DCF on dATP, ATP, NAD, SAH-hydrolase levels and on DNA strand breaks; and (c) the correlation between these parameters with clinical response to DCF. No significant difference in ADA, 5NT, AdR-kinase and SAH-hydrolase activities could be found between responders and non-responders. Incubation of the leukemic cells in vitro with DCF caused an inhibition of ADA, an accumulation of dATP, a moderate reduction in ATP and NAD levels, a suppression of SAH-hydrolase activity and an increase in DNA strand breaks in practically all the leukemic samples, irrespective of clinical response. Our results show that neither measurement of these enzymes nor studies of these biochemical sequelae of ADA inhibition in vitro predicts clinical responsiveness to DCF therapy.

T-cell prolymphocytic leukemia with a novel translocation (6;11)(q21;q23).

T-cell prolymphocytic leukemia (T-PLL) is an uncommon chronic lymphoproliferative disorder characterized by lymphadenopathy, splenomegaly, and lymphocytosis. The leukemic cells have the appearance of prolymphocytes and usually an immunophenotype of T-helper cells (CD3+ CD4+ CD8-). Inv(14q), del(11q), i(8q), and rearranged Xq28 are the commonest nonrandom chromosomal abnormalities in T-PLL. Recently, it has been shown that the ataxia-telangiectasia mutated (ATM) gene located at 11q23 is often deleted in T-PLL, suggesting a tumor suppressor role of the ATM gene on tumorigenesis of T-PLL. We report a case of T-PLL with t(6;11)(q21;q23) as the sole chromosomal abnormality and suggest that the cytogenetically identified translocation also implicates the ATM gene.

[Clinical analysis of 10 patients with chronic lymphoid leukemia].

Ten patients with chronic lymphoid leukemia were analyzed for clinical characteristics, morphology and phenotype of leukemic cells. There were 3 patients with T-chronic lymphocytic leukemia (CLL), 2 with T-prolymphocytic leukemia (PLL), 2 with B-CLL, 1 with B-PLL, 1 with non-T-non-B-CLL and 1 with Waldenström's macroglobulinemia. Although chronic lymphoid leukemia is usually characterized by proliferation of B-lymphocytes, our study revealed that 5 of 10 patients had T-cell phenotype. A peripheral blood specimen of T-CLL showed small lymphocytes with a mature appearance and an irregular nuclear margin. Most of the cells lacked large azurophilic granules in the cytoplasm and nucleoli were also inconspicuous in the nucleus by light and electron microscopic examinations. In PLL, a majority of the cells were large lymphocytes with a prominent nucleolus and abundant basophilic cytoplasm which were more clearly observed by transmitted electron microscopic examination. The patients were treated with cyclophosphamide and prednisolone, but response to treatment was transient. The median survival time was 7 months for all patients, while that of T-cell lineage cases was only 1 month. Therefore, new modalities of treatment must be investigated in the future.

Cerebriform variant type of T cell prolymphocytic leukemia with complex karyotype including an additional segment at 1p36.1.

We describe two patients with T cell prolymphocytic leukemia (T-PLL) who exhibited the same complex karyotype, including an additional segment at 1p36.1. One presented with secondary progression following an initial stable clinical course, and the other with typically progressive disease. Features of the cerebriform variant were identified in the peripheral blood of both patients. Aggressive symptoms, such as lymphocytosis, lymphadenopathy, pleural effusion, cutaneous involvement and hepatosplenomegaly, developed during the progressive phases. Levels of serum soluble interleukin 2 receptor increased when symptoms worsened. These patients did not have the karyotypic 14q11 abnormality and trisomy 8q that are features of non-Japanese patients. The prognoses of these patients were poor; one survived for 2 months and the other survived for 10 months after progression. A chromosomal abnormality may occur in other types of aggressive T-PLL, particularly when extramedullary infiltration is a feature.

Leucemia prolinfocítica T variante de células cerebriformes: presentación de un caso y revisión de la literatura / Cerebriform variant type of T cell prolymphocytic leukemia: report of one case

T cell Prolymphocytic Leukemia (T-PLL) is a rare and aggressive mature T cell Lymphocyte Leukemia. Twenty five percent of cases present as a small cell variant, and only 5% as a cerebriform variant. We report a 58 year-old man with rapidly progressive severe leukocytosis, skin lesions, lymphadenopathy, hepatosplenomegaly and pleural effusion. The lymphocytes had a cerebriform type. The diagnosis of T-PLL variant was made by morphology and immunophenotype study of peripheral blood. Karyotype was found to be complex. He was refractory to chemotherapy and died two months later.

Phase I trial of nelarabine in indolent leukemias.

PURPOSE: To test whether nelarabine is an effective agent for indolent leukemias and to evaluate whether there is a relationship between cellular pharmacokinetics of the analog triphosphate and clinical responses. PATIENTS AND METHODS: Thirty-five patients with relapsed/refractory leukemias (n = 24, B-cell chronic lymphocytic leukemia and n = 11, T-cell prolymphocytic leukemia) were entered onto three different protocols. For schedule A, patient received nelarabine daily for 5 days, whereas for schedule B, nelarabine was administered on days 1, 3, and 5. Schedule C was similar to schedule B except that fludarabine was also infused. Plasma and cellular pharmacokinetics were studied during the first cycle. RESULTS: Responses were achieved in 20%, 15%, and 63% of patients receiving schedule A, B, and C, respectively. Histologic category, number of prior therapies, and fludarabine refractoriness did not influence the response rate. The most common nonhematologic toxicity was peripheral neuropathy. Grade 4 neutropenia and thrombocytopenia complicated 23% and 26% of courses respectively, and were significantly more frequent among patients with pre-existing marrow failure. Pharmacokinetics of plasma nelarabine and arabinosylguanine (ara-G) and of cellular ara-G triphosphate (ara-GTP) were similar in the two groups of diagnoses, and the elimination of ara-GTP from leukemia cells was slow (median, > 24 hours). The median peak intracellular concentrations of ara-GTP were significantly different (P = .0003) between responders (440 micromol/L; range, 35 to 1,438 micromol/L; n = 10) and nonresponders (50 micromol/L; range, 22 to 178 micromol/L; n = 15). CONCLUSION: Nelarabine is an effective regimen against indolent leukemias, and combining it with fludarabine was most promising. Determination of tumor cell ara-GTP levels may provide a predictive test for response to nelarabine.