Central Nervous System Involvement of Natural Killer and T Cell Neoplasms.

PURPOSE OF REVIEW: Peripheral natural killer (NK) and T cell neoplasms comprise approximately 10-15% of non-Hodgkin lymphomas. There are 27 different subtypes of peripheral NK and T cell neoplasms, each of which is relatively uncommon. Treatment has been largely extrapolated from case series, retrospective reports, and paradigms developed for the aggressive B cell lymphomas. This review explores the current knowledge of the characteristics, outcome, and treatment of CNS T cell and NK neoplasms. RECENT FINDINGS: Primary and secondary CNS NK and T cell malignancies confer significant morbidity and poor prognosis. Despite clinical heterogeneity between the 27 subtypes, high-dose methotrexate-based regimens seem most effective overall. The role of prophylaxis against secondary CNS involvement remains controversial. Autologous stem cell transplant and immunotherapy are potential for promising future therapies. Current understanding of incidence, outcome, and optimal treatment strategies for CNS T cell and NK neoplasms is limited, in large part due to their diversity and rarity. Prognosis is poor, except in a few reports of long-term survival in patients most often treated with combination therapy including high-dose methotrexate. A future prospective study on treatment and outcome in CNS T cell and NK neoplasms is needed to better define these diseases.

Akt2 mediates glucocorticoid resistance in lymphoid malignancies through FoxO3a/Bim axis and serves as a direct target for resistance reversal.

Glucocorticoids (GCs) are widely used drugs in the treatment of lymphoid malignancies; resistance of GCs in lymphocytes confers poor prognosis and the mechanisms are poorly understood. Here, we found T-acute lymphoblastic leukemia (T-ALL) cells acquire resistance to dexamethasone (DEX)-mediated killing through abnormal activation of Akt, resulting in inhibition of the FoxO3a/Bim pathway. The resistant state was reported to be associated with increased glycolysis, NOTCH1 activating mutations and activated PI3K/ serum GS regulated kinases (SGK) pathway. Use of aforementioned pathway inhibitors blocked FoxO3a-phosphorylation and partially improved DEX-mediated killing of GC-resistant T-ALL cells, further revealing the essential role of the FoxO3a/Bim pathway in the development of GC resistance. Inhibition of Akt is most effective at restoring sensitivity to DEX of GC-resistant lymphocytes in vitro and in vivo, but shows significant hepatotoxicity in vivo. A significantly elevated expression of Akt2 not Akt1 in intrinsically, secondarily GC-resistant lymphocytes and relapsed/refractory ALL patients implicates a more specific target for GC resistance. Mechanistically, Akt2 has a stronger binding capacity with FoxO3a compared to Akt1, and acts as a direct and major negative regulator of FoxO3a activity driving GC resistance. Pharmacologic inhibition of Akt2 more effectively restores sensitivity to GCs than inhibition of Akt1 in vitro, shows higher synergistic effect acting with DEX, and reverses GC resistance in GC-resistant T- or B- lymphoid tumors in vivo with reduced liver toxicity. In summary, these results suggest that Akt2 might serve as a more direct and specific kinase mediating GC resistance through FoxO3a/Bim signaling pathway, and Akt2 inhibition may be explored as a promising target for treating GC-resistant hematopoietic malignancies.

Sobrevida global de pacientes con leucemia aguda en el Hospital de Especialidades Pediátricas de Chiapas, México / Childhood acute leukemia overall survival at the Hospital de Especialidades Pediátricas in Chiapas, México

Resumen: Introducción: A 10 años de la fundación del Hospital de Especialidades Pediátricas en Chiapas, México, es importante valorar la sobrevida global a 5 años de los pacientes con leucemia aguda bajo el régimen del Seguro Popular. Métodos: Estudio descriptivo y de sobrevida de 210 casos de leucemia aguda diagnosticados y tratados entre 2008 y 2012. Empleando curvas de Kaplan-Meier se analizó cada variedad de la enfermedad (B, T y mieloide), y para la leucemia B en función del grupo de riesgo, el sexo, la edad, los leucocitos al diagnóstico, los marcadores de superficie, el índice de DNA, el cariotipo y las translocaciones. Resultados: La edad, el sexo y la proporción de tipos de leucemia aguda (B = 85%; M = 10%; T = 5%) fueron similares al resto del país. El 20% de los pacientes estaban vivos a 5 años; el 53% habían fallecido y el 27% abandonaron el tratamiento. La sobrevida global a 5 años fue del 42% (B = 45%; T = 20%; M = 10%) (mediana: 38.8 meses; intervalo de confianza del 95%: 28.9-48.7). La mediana de «muy alto riesgo¼ fue de 7.7 contra 47 meses; no hubo diferencia entre riesgo habitual y alto riesgo. Los leucocitos < 50,000/µl al diagnóstico y CD10 positivo se asociaron con mejor sobrevida. En el momento del deceso, el 29% se encontraba en remisión. Conclusiones: La sobrevida de la leucemia aguda bajo el Seguro Popular fue desfavorable los primeros 5 años del Hospital de Especialidades Pediátricas. Se identificaron como contribuyentes la alta tasa de mortalidad temprana, de pacientes en remisión y el abandono. Además de revisar la atención médica, se requiere el estudio de elementos extrahospitalarios determinantes del abandono para mejorar el programa.

Abstract: Background: At the 10th anniversary of the Hospital de Especialidades Pediátricas in Chiapas, Mexico, it was important to assess the 5-year acute leukemia overall survival under the Seguro Popular program (Popular Insurance). Methods: A descriptive and survival study of 210 acute leukemia patients diagnosed and treated during 2008-2012 was performed. Kaplan-Meier survival curves were developed for all patients, each leukemia type (B, T and myeloid) and for B type related to risk group, age, sex, leukocytes, cell markers, DNA index, karyotype, and translocations. Results: Age, gender and proportion of leukemia types (B = 85%; M = 10%; T = 5%), were similar to other parts of the country. At the end of the 5-year treatment, 20% of the patients were alive, 53% had died and 27% had abandoned the treatment. Global survival was 42% (B = 45%; T = 20%; M = 10%) (median: 38.8 months; confidence interval of 95% = 28.9-48.7). Very high-risk median survival was 7.7 versus 47 months. There was no difference between standard and high-risk groups. The initial leukocyte count < 50,000/µL and CD10 positive were related to better B survival; no other variables were related. At the time of death, 29% of patients were in remission. Conclusions: Global survival of acute leukemia at Hospital de Especialidades Pediátricas under the Seguro Popular during its first 5 years was surprisingly poor given the medical resources available through the insurance. Early mortality, death during remission and high desertion rates contributed to these results. A detailed revision of treatment protocols and reasons for abandoning treatment is mandatory.

[Sobrevida global de pacientes con leucemia aguda en el Hospital de Especialidades Pediátricas de Chiapas, México]. / Childhood acute leukemia overall survival at the Hospital de Especialidades Pediátricas in Chiapas, México.

Background: At the 10th anniversary of the Hospital de Especialidades Pediátricas in Chiapas, Mexico, it was important to assess the 5-year acute leukemia overall survival under the Seguro Popular program (Popular Insurance). Methods: A descriptive and survival study of 210 acute leukemia patients diagnosed and treated during 2008-2012 was performed. Kaplan-Meier survival curves were developed for all patients, each leukemia type (B, T and myeloid) and for B type related to risk group, age, sex, leukocytes, cell markers, DNA index, karyotype, and translocations. Results: Age, gender and proportion of leukemia types (B = 85%; M = 10%; T = 5%), were similar to other parts of the country. At the end of the 5-year treatment, 20% of the patients were alive, 53% had died and 27% had abandoned the treatment. Global survival was 42% (B = 45%; T = 20%; M = 10%) (median: 38.8 months; confidence interval of 95% = 28.9-48.7). Very high-risk median survival was 7.7 versus 47 months. There was no difference between standard and high-risk groups. The initial leukocyte count < 50,000/mL and CD10 positive were related to better B survival; no other variables were related. At the time of death, 29% of patients were in remission. Conclusions: Global survival of acute leukemia at Hospital de Especialidades Pediátricas under the Seguro Popular during its first 5 years was surprisingly poor given the medical resources available through the insurance. Early mortality, death during remission and high desertion rates contributed to these results. A detailed revision of treatment protocols and reasons for abandoning treatment is mandatory.

Introducción: A 10 años de la fundación del Hospital de Especialidades Pediátricas en Chiapas, México, es importante valorar la sobrevida global a 5 años de los pacientes con leucemia aguda bajo el régimen del Seguro Popular. Métodos: Estudio descriptivo y de sobrevida de 210 casos de leucemia aguda diagnosticados y tratados entre 2008 y 2012. Empleando curvas de Kaplan-Meier se analizó cada variedad de la enfermedad (B, T y mieloide), y para la leucemia B en función del grupo de riesgo, el sexo, la edad, los leucocitos al diagnóstico, los marcadores de superficie, el índice de DNA, el cariotipo y las translocaciones. Resultados: La edad, el sexo y la proporción de tipos de leucemia aguda (B = 85%; M = 10%; T = 5%) fueron similares al resto del país. El 20% de los pacientes estaban vivos a 5 años; el 53% habían fallecido y el 27% abandonaron el tratamiento. La sobrevida global a 5 años fue del 42% (B = 45%; T = 20%; M = 10%) (mediana: 38.8 meses; intervalo de confianza del 95%: 28.9-48.7). La mediana de «muy alto riesgo¼ fue de 7.7 contra 47 meses; no hubo diferencia entre riesgo habitual y alto riesgo. Los leucocitos < 50,000/ml al diagnóstico y CD10 positivo se asociaron con mejor sobrevida. En el momento del deceso, el 29% se encontraba en remisión. Conclusiones: La sobrevida de la leucemia aguda bajo el Seguro Popular fue desfavorable los primeros 5 años del Hospital de Especialidades Pediátricas. Se identificaron como contribuyentes la alta tasa de mortalidad temprana, de pacientes en remisión y el abandono. Además de revisar la atención médica, se requiere el estudio de elementos extrahospitalarios determinantes del abandono para mejorar el programa.

Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors.

Three distinct immature T-cell acute lymphoblastic leukemia entities have been described including cases that express an early T-cell precursor immunophenotype or expression profile, immature MEF2C-dysregulated T-cell acute lymphoblastic leukemia cluster cases based on gene expression analysis (immature cluster) and cases that retain non-rearranged TRG@ loci. Early T-cell precursor acute lymphoblastic leukemia cases exclusively overlap with immature cluster samples based on the expression of early T-cell precursor acute lymphoblastic leukemia signature genes, indicating that both are featuring a single disease entity. Patients lacking TRG@ rearrangements represent only 40% of immature cluster cases, but no further evidence was found to suggest that cases with absence of bi-allelic TRG@ deletions reflect a distinct and even more immature disease entity. Immature cluster/early T-cell precursor acute lymphoblastic leukemia cases are strongly enriched for genes expressed in hematopoietic stem cells as well as genes expressed in normal early thymocyte progenitor or double negative-2A T-cell subsets. Identification of early T-cell precursor acute lymphoblastic leukemia cases solely by defined immunophenotypic criteria strongly underestimates the number of cases that have a corresponding gene signature. However, early T-cell precursor acute lymphoblastic leukemia samples correlate best with a CD1 negative, CD4 and CD8 double negative immunophenotype with expression of CD34 and/or myeloid markers CD13 or CD33. Unlike various other studies, immature cluster/early T-cell precursor acute lymphoblastic leukemia patients treated on the COALL-97 protocol did not have an overall inferior outcome, and demonstrated equal sensitivity levels to most conventional therapeutic drugs compared to other pediatric T-cell acute lymphoblastic leukemia patients.

Implication of IRF4 aberrant gene expression in the acute leukemias of childhood.

The most frequent targets of genetic alterations in human leukemias are transcription factor genes with essential functions in normal blood cell development. The Interferon Regulatory Factor 4 (IRF4) gene encodes a transcription factor important for key developmental stages of hematopoiesis, with known oncogenic implications in multiple myeloma, adult leukemias and lymphomas. Very few studies have reported an association of IRF4 with childhood malignancy, whereas high transcript levels have been observed in the more mature immunophenotype of ALL. Our aim was to investigate the expression levels of IRF4 in the diagnostic samples of pediatric leukemias and compare them to those of healthy controls, in order to determine aberrant gene expression and whether it extends to leukemic subtypes other than the relatively mature ALL subpopulation. Quantitative real-time RT-PCR methodology was used to investigate IRF4 expression in 58 children with acute leukemias, 4 leukemic cell lines and 20 healthy children. We show that aberrant IRF4 gene expression is implicated in a variety of leukemic subtypes; higher transcript levels appear in the more immature B-common ALL subtype and in T-cell than in B-cell leukemias, with the highest expression levels appearing in the AML group. Interestingly, we show that childhood leukemia, irrespective of subtype or cell maturation stage, is characterised by a minimum of approximately twice the amount of IRF4 gene expression encountered in healthy children. A statistically significant correlation also appeared to exist between high IRF4 expression and relapse. Our results show that ectopic expression of IRF4 follows the reverse expression pattern of what is encountered in normal B-cell development and that there might be a dose-dependency of childhood leukemia for aberrantly expressed IRF4, a characteristic that could be explored therapeutically. It is also suggested that high IRF4 expression might be used as an additional prognostic marker of relapse at diagnosis.

Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia.

BACKGROUND: Molecular alterations occur frequently in T-ALL and the potential impact of those abnormalities on outcome is still controversial. The current study aimed to test whether NOTCH1 mutations and additional molecular abnormalities would impact T-ALL outcome in a series of 138 T-ALL paediatric cases. METHODS: T-ALL subtypes, status of SIL-TAL1 fusion, ectopic expression of TLX3, and mutations in FBXW7, KRAS, PTEN and NOTCH1 were assessed as overall survival (OS) and event-free survival (EFS) prognostic factors. OS and EFS were determined using the Kaplan-Meier method and compared using the log-rank test. RESULTS: The frequencies of mutations were 43.5% for NOTCH1, while FBXW7, KRAS and PTEN exhibited frequencies of 19.1%, 9.5% and 9.4%, respectively. In 78.3% of cases, the coexistence of NOTCH1 mutations and other molecular alterations was observed. In multivariate analysis no statistical association was revealed between NOTCH1 mutations and any other variable analyzed. The mean length of the follow-up was 68.4 months and the OS was 50.7%. SIL-TAL1 was identified as an adverse prognostic factor. NOTCH1 mutation status was not associated with outcome, while the presence of NOTCH1 complex mutations (indels) were associated with a longer overall survival (p = 0.031) than point mutations. CONCLUSION: NOTCH1 mutations alone or in combination with FBXW7 did not impact T-ALL prognosis. Nevertheless, complex NOTCH1 mutations appear to have a positive impact on OS and the SIL-TAL1 fusion was validated as a negative prognostic marker in our series of T-ALL.

Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia.

Although deletions of cell cycle regulatory gene loci have long been reported in various malignancies, little is known regarding their relevance in pediatric T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (TALL). The current study focused on loss of heterozygosity (LOH) analyses of the CDKN2A/B (chromosome 9p), ATM (chromosome 11q) and p53 (chromosome 17p) gene loci. Frequencies of LOH were compared in 113 pediatric T-LBL and 125 T-ALL who were treated uniformly according to ALL-BFM strategies. Furthermore, LOH findings were correlated with clinical characteristics and tested for their prognostic relevance. LOH at 9p was detected in 47% of T-LBL and 51% of T-ALL, and was associated with male gender in both. In T-ALL, LOH at 9p was associated with favorable initial treatment response. A tendency for favorable event-free-survival was observed in LOH 9p positive T-LBL. The frequency of LOH at chromosomes 11q and 17p was 5% or less for both diseases.

Low frequency of Epstein Barr virus association and high frequency of p53 overexpression in an Argentinean pediatric T-cell lymphoma series.

T-cell non-Hodgkin's lymphomas (NHLs) represent 10% to 15% of all diagnosed lymphomas in Western countries. Various geographic frequencies of T-cell NHL have been documented, in part reflecting increased exposure to pathogenic factors such as Epstein-Barr virus (EBV). Our aims were to assess EBV and p53 expression in Argentine pediatric T-cell lymphoma and to correlate them with patients' survival. Epstein-Barr encoded RNAs (EBERs) in situ hybridization and LMP1 and p53 immunohistochemical staining were performed on formalin-fixed paraffin-embedded lymph node biopsies from 25 pediatric T-lymphoma patients. In 17 of 25 samples good-quality DNA was obtained, and EBER polymerase chain reaction was assessed to confirm in situ hybridization and immunohistochemical results. Epstein-Barr virus expression was found in 8.0% of cases. p53-positive staining was distributed in 92% of pediatric cases. Kaplan-Meier survival analysis showed that neither EBV nor p53 expression was statistically significantly associated with event-free survival. Our data showed a low frequency of EBV association with pediatric T-cell lymphoma. It seems that p53 plays an important role in proliferation in our studied population, since it is overexpressed in 92% of T-cell lymphoma cases.

Prevalence and clinical relevance of autoimmune neutropenia in patients with primary Sjögren's syndrome.

OBJECTIVE: To analyze the prevalence of neutropenia in a large cohort of patients with primary Sjögren's syndrome (SS) and its association with clinical and immunological disease expression and adverse outcomes. METHODS: The study cohort included 300 patients diagnosed with primary SS in our department between 1984 and 2002. The outcomes measured after the first laboratory evidence of neutropenia (<2.5 x 10(9)/L) were first hospital admission caused by infection, development of systemic manifestations, neoplasia, and death. RESULTS: Ninety-nine (33%) patients had neutropenia during the follow-up, which was related to neoplasia or drugs in 9 (3%) patients and was considered idiopathic in the remaining 90 (30%). Patients with neutropenia had a lower mean age at diagnosis of SS (51.9 versus 59.4 years, P < 0.001) and a higher prevalence of anti-Ro/La antibodies (53% versus 22%, P < 0.001), rheumatoid factor (49% versus 32%, P = 0.009), and low C4 levels (17% versus 8%, P = 0.044) than those without neutropenia. Patients with neutropenia had a higher incidence of hospital admission caused by infection (24% versus 9%, P = 0.002), especially those with neutropenia <1 x 10(9)/L (50% versus 9%, P = 0.002), and a higher rate of admission (log rank = 0.0023) in comparison with those without neutropenia. Agranulocytosis was found in 7 (2%) patients, predominantly related to neoplasia (5 cases). One (1%) of the 90 patients with SS-related neutropenia developed large granular lymphocyte T-cell leukemia. CONCLUSION: Neutropenia should be considered a relevant hematologic finding of primary SS, due both to its elevated prevalence and to its clinical significance (close association with anti-Ro/La antibodies, coexistence with other cytopenias, and development of severe infections).

Anemia and survival in childhood acute lymphoblastic leukemia.

BACKGROUND: Several studies have demonstrated that patients with childhood acute lymphoblastic leukemia presenting with mild anemia at diagnosis have an increased risk of poor outcome compared to patients with more severe anemia. However, it has not been reported whether there is any correlation between degree of anemia and leukemia subtype. DESIGN AND METHODS: In a cohort of 1162 patients with childhood acute lymphoblastic leukemia we analyzed whether there was a correlation between degree of anemia and leukemia subtype. We also studied the association between degree of anemia and event-free survival within the subtypes. RESULTS: Hemoglobin levels at diagnosis were distributed in a non-random pattern. The degree of anemia was significantly different for three distinct groups of patients compared to the remaining patients (mean hemoglobin; T-cell leukemia: 106 g/L versus 76 g/L (precursor B-cell acute lymphoblastic leukemia); within precursor B-cell ALL: TEL-AML1 positive: 68 g/L versus 79 g/L; BCR-ABL positive: 93 g/L versus 76 g/L; each p<0.05). Furthermore, in contrast to the entire study group, patients with T-cell leukemia, TEL-AML1(+), and BCR-ABL(+) precursor B-cell leukemia had a more favorable prognosis if presenting with a higher hemoglobin level (>/=80 g/L). CONCLUSIONS: These observations indicate that the formerly reported direct correlation between severity of anemia and survival in childhood acute lymphoblastic leukemia mainly reflects differences in the degree of anemia between distinct biological subgroups with different treatment outcomes. On the other hand, the inverse relationship between severity of anemia and survival found within specific subgroups suggests that very low hemoglobin levels at diagnosis are associated with more advanced disease in these subgroups.

T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive post-thymic malignancy with poor response to conventional treatment and short survival. It can readily be distinguished from other T-cell leukemias on the basis of the distinctive morphology, immunophenotype, and cytogenetics. Consistent chromosomal translocations involving the T-cell receptor gene and one of two protooncogenes (TCL-1 and MTCP-1) are seen in the majority of cases and are likely to be involved in the pathogenesis of the disorder. The CD52 antigen is expressed at high density on the malignant T-cells and therapy with alemtuzumab, a humanized IgG1 antibody that targets this antigen, has produced promising results. In relapsed/refractory patients overall and complete response rates have been seen in up to 76% and 60%, respectively. In previously untreated patients, complete remission rates of 100% have been reported. These responses are durable and translate into improved survival for responders. However, relapse is inevitable and strategies using both autologous and allogeneic stem cell transplantation are currently being explored. Additional clinical trials are investigating the use of alemtuzumabin combinations with chemotherapy, either concurrent or sequential. In the future we hope to have a betterunderstanding of how best to integrate these therapeutic approaches to further prolong survival for patients with T-PLL.

Purine analogues in advanced T-cell lymphoid malignancies.

T-cell lymphomas account for 10% to 15% of all lymphoid malignancies. In advanced stages of T-cell lymphoma, single or multiagent chemotherapy and bioimmunotherapeutic agents have been used. Purine analogues have demonstrated activity in both refractory cutaneous T-cell lymphoma and peripheral T-cell lymphoma with response rates ranging from 20% to 70%. Response rates have been higher with pentostatin (60%) than with the other compounds in this class. The potential limitation to this therapy is the prolonged immunosuppression, which increases the risk of opportunistic injections in patients who are already at heightened risk for infections. Patients should be monitored closely with CD4 counts and surveillance for opportunistic infections. Future studies of purine analogues should evaluate patients who are less heavily pretreated and combination therapy with other agents such as alemtuzumab should be investigated in order to prolong the duration of disease remission.

Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group.

PURPOSE: Nelarabine (compound 506U78), a water soluble prodrug of 9-b-d-arabinofuranosylguanine, is converted to ara-GTP in T lymphoblasts. We sought to define the response rate of nelarabine in children and young adults with refractory or recurrent T-cell disease. PATIENTS AND METHODS: We performed a phase II study with patients stratified as follows: stratum 1: > or = 25% bone marrow blasts in first relapse; stratum 2: > or = 25% bone marrow blasts in > or = second relapse; stratum 3: positive CSF; stratum 4: extramedullary (non-CNS) relapse. The initial nelarabine dose was 1.2 g/m2 daily for 5 consecutive days every 3 weeks. There were two dose de-escalations due to neurotoxicity on this or other studies. The final dose was 650 mg/m2/d for strata 1 and two patients and 400 mg/m2/d for strata 3 and four patients. RESULTS: We enrolled 121 patients (106 assessable for response) at the final dose levels. Complete plus partial response rates at the final dose levels were: 55% in stratum 1; 27% in stratum 2; 33% in stratum 3; and 14% in stratum 4. There were 31 episodes of > or = grade 3 neurologic adverse events in 27 patients (18% of patients). CONCLUSION: Nelarabine is active as a single agent in recurrent T-cell leukemia, with a response rate more than 50% in first bone marrow relapse. The most significant adverse events associated with nelarabine administration are neurologic. Further studies are planned to determine whether the addition of nelarabine to front-line therapy for T-cell leukemia in children will improve survival.

Clinical significance of central nervous system involvement at diagnosis of childhood T-cell acute lymphoblastic leukemia.

BACKGROUND: Patients with T-cell acute lymphoblastic leukemia (T-ALL) frequently present with unfavorable features at diagnosis. Therefore, they are considered to have a higher risk to relapse. We sought to correlate initial central nervous system (CNS) disease at diagnosis with shortened survival in childhood T-ALL. PROCEDURE: A retrospective analysis of 48 children with T-ALL was performed. The group consisted of 32 boys and 16 girls whose median age was 8 years. Their CNS status was classified as CNS-1 (no blast cells in cerebrospinal fluid (CSF); n = 44), CNS-2 (<5 WBC/microl of CSF with blast cells; n = 0), or CNS-3 (> or =5 WBC/microl of CSF with blast cells or signs of CNS involvement; n = 4). For univariate prognostic analyses, we used the log-rank test to determine the influence of patient characteristics (age, sex, lymphomatous presentations, initial leukocyte count, CNS disease, and newer therapeutic strategies) on each point. RESULTS: Complete remission was induced in 87.5% of patients. Median survival was 37 months, and 5-year overall survival and disease-free survival rates were 49.5% +/- 8.1% and 47.1% +/- 8.2%, respectively. Patients without initial CNS involvement seemed to have a trend toward longer overall survival (P = 0.036). Disease-free survival was not influenced by age, leukocyte count, or other factors analyzed. CONCLUSIONS: Patients who present with initial CNS involvement have a prognosis worse than that of patients without CNS disease. The introduction of early and effective CNS-directed therapy might no longer portend a poor prognosis for CNS leukemia.

T-cell prolymphocytic leukemia involving extramedullary sites.

T-cell prolymphocytic leukemia (T-PLL) can involve extramedullary sites, but the diagnosis is usually established by examination of blood and bone marrow. As a result, the histologic findings at extramedullary sites are poorly documented in the literature. We describe 19 extramedullary biopsy specimens from 14 patients with T-PLL. Skin (n = 10) was the most common site biopsied. T-PLL surrounded dermal blood vessels and appendages (n = 6), diffusely replaced dermis (n = 3), or formed a subcutaneous mass (n = 1). Other extramedullary sites included liver and lymph nodes (3 each) and spleen, lung, and cecum (1 each). In liver and lymph nodes, the neoplasm predominantly involved portal tracts and paracortex, respectively. Cytologically, the T-PLL cells were round (n = 16) or Sezary cell-like (n = 3). Nucleoli were observed in a subset of cells in 8 specimens and were prominent in 3 specimens. Immunostaining for T-cell leukemia-1 (TCL-1) was positive in specimens from 9 (64%) of 14 patients. We conclude that the prolymphocytoid features of T-PLL cells can be difficult to detect in routinely stained sections of extramedullary biopsy specimens. TCL-1 expression can aid in diagnosis at extramedullary sites.

Alemtuzumab in peripheral T-cell malignancies.

The humanized monoclonal antibody CAMPATH-1H (alemtuzumab) binds to the CD52 antigen, a glycoprotein that is widely expressed on normal and malignant B- and T-lymphocytes. Over the past 5 years, a number of trials have demonstrated that alemtuzumab has clinical activity in mature T-cell diseases such as T-cell prolymphocytic leukemia (T-PLL) and cutaneous T-cell lymphoma (CTCL). In heavily pretreated relapsed/refractory patients alemtuzumab induced responses in more than two thirds of T-PLL and more than 50% of CTCL patients. Responding patients had improved survival compared to nonresponders. Alemtuzumab is particularly effective in clearing malignant lymphocytes from peripheral blood and bone marrow and may therefore facilitate stem-cell transplantation (SCT) in selected patients. The toxicity profile for the antibody is acceptable; the major complications are infusional reactions, which generally subside after the first 1-2 weeks of therapy, and prolonged lymphopenia associated with reactivation of viruses. These can be minimized by careful monitoring and the use of prophylactic therapy. Future studies will be directed toward: alternative routes (subcutaneous) and schedules of administration; use as first-line therapy; combination strategies with conventional chemotherapy; and use of alemtuzumab to purge minimal residual bone-marrow disease prior to SCT.

Rapid tumor death model for evaluation of new therapeutic agents for adult T-cell leukemia.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm. The health of ATL patients rapidly deteriorates resulting in death; however, the induction of death in a small animal model due to tumor has not yet been reported. SCID mice, 5 weeks old, younger than those previously used, which were inoculated with ATL cells, eliminated NK cell activity and showed rapid tumor formation resulting in death. Age is the crucial factor influencing tumor formation and death in the SCID mice model for cancer.

Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951.

In a series of 153 children with T-cell malignancies enrolled in 2 consecutive European Organization for Research and Treatment of Cancer (EORTC) trials, we assessed the HOX11L2 expression and/or the presence of a t(5;14)(q35;q32). Additionally, in 138 of these patients, HOX11 expression and SIL-TAL rearrangement were also assessed. These alterations were mutually exclusive, and their frequency was 23% (n = 35), 7% (n = 10), and 12% (n = 17), respectively. HOX11L2/t(5;14) positivity was more frequent in acute lymphoblastic leukemia (ALL) with cortical T immunophenotype and in children aged between 6 and 9 years. In contrast with previously reported data, patients positive and negative for HOX11L2/t(5;14) were comparable with regard to clinical outcome as well as to the response to a 7-day prephase treatment or to residual disease at completion of induction therapy. The 3-year event-free survival (EFS) rate (+/- SE percentage) for patients positive and negative for HOX11L2/t(5;14) was 75.5% (+/- 8.1%) and 68.3% (+/- 5.0%), respectively; the hazard ratio was 0.84 (95% confidence interval, 0.40-1.80). Patients with HOX11-high expression and those with SIL-TAL fusion had low levels of residual disease at the end of induction and a favorable prognosis: the 3-year EFS rate was 83.3% (+/- 8.5%) and 75.3% (+/- 12.6%), respectively. The results obtained in HOX11L2/t(5;14) patients in this study do not confirm the unfavorable prognosis reported in previous studies.

Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome.

Adult T-cell leukemia/lymphoma (ATLL) is a distinct clinical entity among mature T-cell neoplasms, and its causative agent has been confirmed to be long-term infection by human T-lymphotropic virus type 1. A recent study demonstrated frequent expression of a chemokine receptor, CC chemokine receptor (CCR)4, which is known as a Th2 marker but not CXC chemokine receptor (CXCR)3, which is known as a Th1 marker, among both ATLL- and human T-lymphotropic virus type 1-immortalized T cells. In this study, immunostaining analysis for CCR4 and CXCR3 expression in ATLL cells obtained from 103 patients with ATLL was performed, and the clinical parameters and overall survival of the CCR4-positive and -negative cases were compared. Ninety-one (88.3%) of the 103 cases were positive for CCR4 staining, whereas only 5 (4.9%) were positive for CXCR3 staining. Positivity for CCR4 was significantly associated with skin involvement (P < 0.05), although there were no significant differences in clinical characteristics between the CCR4-positive and -negative cases at the time of initial diagnosis. CCR4(+) ATLL cells may accumulate in the skin because of the expression of a CCR4 ligand, thymus and activation-regulated chemokine (TARC), on normal and inflamed cutaneous endothelia. As for survival analysis, positivity for CCR4 expression was extracted as an unfavorable prognostic factor as well as other factors, including the presence of B symptoms and extranodal involvement of more than one site. Multivariate analysis confirmed that CCR4 expression was an independent and significant prognostic factor (P < 0.05). Thus, our finding may provide a novel insight into not only the biological but also the clinical features of ATLL.