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.

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.

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.

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.

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.

[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.

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.

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.

Intratesticular transplantation of testicular cells from leukemic rats causes transmission of leukemia.

A rat T-cell leukemia model was used to study the safety of germ cell transplantation as a mean of preventing infertility in males undergoing gonadotoxic cancer treatment. Donor germ cells were harvested from the testes of terminally ill leukemic rats and were either used directly or cryopreserved and thawed before transplantation by rete testis microinjection. All rats transplanted with testicular cells from leukemic donors developed signs of terminal rat T-cell leukemia, whereas control animals remained healthy. Cryopreservation of the donor germ cells caused a 3- to 6-day delay in the terminal phase of leukemia. When a known number of leukemic cells were mixed with germ cells and microinjected into the testis, the rate of appearance of terminal leukemia was directly related to the number of transferred leukemic lymphoblasts. As few as 20 leukemic cells were able to cause a cancer relapse resulting in terminal leukemia 21 days after transplantation in three of five transplanted animals. Our results demonstrate that germ cell transplantation with the presently used techniques is not safe enough for clinical use. Improved methods for purging testicular specimens of cancer cells or totally new approaches with transient xenogenetic host models to detect contamination of malignant cells must be developed before this technique can be offered to patients without fear of disease relapse.

Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed.

PURPOSE: We conducted a retrospective analysis to evaluate the safety and efficacy of Campath-1H, an anti-CD52 humanized monoclonal antibody, in previously treated T-prolymphocytic leukemia (T-PLL) patients in a compassionate-use program. PATIENTS AND METHODS: Seventy-six patients with T-PLL (including four chemotherapy-naive patients) received 3, 10, and 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly, as 2-hour intravenous infusions, for 4 to 12 weeks. RESULTS: Median patient age was 60 years (range, 35 to 84). Spleen liver, lymph node, and skin involvement were present in 64%, 40%, 54%, and 18% of patients, respectively. All tested patients had CD2, CD7, CD4, and/or CD8 positivity, whereas CD5 and CD3 were positive in 98% and 96% of tested patients, respectively. The objective response rate was 51% (95% confidence interval [CI], 40% to 63%), with a 39.5% complete response (CR) rate (95% CI, 28% to 51%). The median duration of CR was 8.7 months (range, 0.13+ to 44.4), and median time to progression was 4.5 months (range, 0.1 to 45.4) compared with 2.3 months (range, 0.2 to 28.1) after first-line chemotherapy. The median overall survival was 7.5 months (14.8 months for CR patients). The most common Campath-1H-related adverse events were acute reactions during or immediately after infusions. Fifteen infectious episodes occurred during treatment in 10 patients (13%), leading to treatment discontinuation in three. Eight patients experienced possibly related, late-onset infections. Severe thrombocytopenia and/or neutropenia occurred in six patients (8%), leading to treatment discontinuation in four. Two treatment-related deaths occurred. CONCLUSION: Campath-1H is an active drug in T-PLL patients for whom first-line therapy has failed. It has a favorable risk/benefit ratio and should be prospectively investigated in chemotherapy-naive patients.

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.

Detection of T-cell receptor delta gene rearrangement by clonal specific polymerase chain reaction.

A sensitive and specific technique to detect minimal residual disease for T-cell malignancies was explored. Southern analysis and polymerase chain reaction (PCR) were used to detect the rearranged V-D-J segment of T-cell receptor delta (TCR delta) gene from malignant cell specimens of patients with leukemia and lymphoma of T-cell lineage. The PCR product was sequenced and from the DNA sequences of the V-D-J region, a 3' antisense primer was designed and synthesized for clonal specific PCR (CS-PCR). Seven of the 22 T-ALL (32%) and 5 of 18 (28%) T-cell lymphoma showed clonal rearrangement by Southern analysis. Six of the 7 (86%) T-ALL and 4 of the 5 (80%) T-cell lymphoma which were Southern positive were also positive by TCR delta PCR. The PCR products of four cases of T-ALL showing clonal pattern by TCR delta PCR amplification were successfully sequenced and CS-PCR amplification performed. CS-PCR detected with confidence specific clonal rearrangement in a mixture containing 0.003% of malignant cells. Marrow specimens obtained at diagnosis and subsequent follow-ups from the 4 T-ALL patients were studied by Southern analysis, TCR delta PCR and CS-PCR. The first patient was in continuous morphological complete remission for more than 3 years and had persistently negative Southern, TCR delta PCR and CS-PCR results on follow-up. Initial follow-up marrow samples from the second patient had persistently positive CS-PCR results while they were still morphologically and TCR delta PCR negative and the patient had a frank leukemic relapse at 18 months. The other two patients had persistent disease by conventional morphological examination, Southern analysis, TCR delta PCR and CS-PCR studies were all positive as expected. CS-PCR is a highly specific and sensitive technique in detecting minimal residual disease for T-cell malignancies. Its potential applications warrant further clinical evaluation and correlation.

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.

DNA aneuploidy of adult T-cell leukemia cells.

To clarify the biological characteristics of adult T-cell leukemia (ATL), immunophenotyping and DNA aneuploid analysis were performed in 72 ATL cases, using flow cytometric techniques. DNA aneuploidy was found in 45 cases (62.5%); the DNA index ranged from 1.03 to 2.16 (mean: 1.24). The incidence of aneuploidy in smoldering, chronic, acute, and lymphoma ATL subtypes was 20.0%, 46.6%, 76.3%, and 77.8%, respectively. The aneuploid patients had a greater tumor burden (adenopathy, hepatosplenomegaly, and leukocytosis with ATL cells), a higher level of serum LDH, and a higher incidence of hypercalcemia, compared with the diploid group. Further, unusual aberrant immunophenotypes were identified predominantly in the aneuploid group. Patients with aneuploidy had a 7.6 month median survival time (MST) with a 2 year survival rate of 24.6%, significantly worse than in the patients with diploidy, whose MST was 25.4 months with a 2 year survival of 60.1%. In some aneuploid patients, the disease often progresses from a static to an aggressive form. Thus, the determination of aneuploidy and unusual immunophenotype should be useful for detecting clinical behavior and for monitoring ATL patients, particularly in regard to such progression.

Phenotypic diversity and prognosis of adult T-cell leukemia.

We examined phenotypically 107 patients with adult T-cell leukemia (ATL), using a panel of monoclonal antibodies, in order to clarify the occurrence of aberrant phenotypes, and to determine the correlation between phenotypic diversity and prognosis. The incidence of the typical (CD4+.CD8-) phenotype, the double-negative (CD4-.CD8-), the double-positive (CD4+.CD8+), and the CD8-positive (CD4-.CD8+) phenotypes was 81%, 7%, 7%, and 4%, respectively. The median survival time (MST) for all patients was 10.0 months with 17% survival at 2 years. The patients with typical phenotypes had a 10.2 month MST with 20% survival at 2 years, significantly better than the patients with the unusual phenotypes whose MST were 4.9, 7.8, and 2.6 months, respectively, for the double-negative, double-positive, and CD8-positive phenotypes. Lack of antigens reactive with CD2, CD3, CD5, and WT31 monoclonal antibody panels was one factor in bad prognosis, but the presence of CD4 and CD8 antigen abnormalities was much more significant.

High-dose daunorubicin as liposomal compound (Daunoxome) in elderly patients with acute lymphoblastic leukemia.

Elderly acute lymphoblastic leukemia (ALL) is a rare condition associated with low complete remission (CR) rate and short survival. In order to improve these results, we evaluate the efficacy and toxicity of Daunoxome, a liposomal daunorubicin, exhibiting toxicity profile and pharmacokinetic indices better than standard daunorubicin. In total, 15 consecutive patients with nonmature ALL were enrolled on a prospective phase II study. No exclusion was made because of older age, poor performance status and organ dysfunctions. Median age was 69 years; performance status resulted >/=2 in nine patients (60%), six patients (40%) were bcr-abl positive and two-thirds of the patients had comorbidities. Induction therapy consisted of vincristine, Daunoxome and dexamethasone. Patients in CR received one or two consolidation cycles of cyclophosphamide, cytarabine and topotecan followed, in patients achieving CR, by a two-year rotating maintenance course including vincristine, Daunoxome, cyclophosphamide and prednisone. In all, 11 patients (73%) achieved CR, three patients (20%) died early during the induction phase and one patient (7%) had resistant disease. Five patients (33%) relapsed after 5-21 months. With a median follow-up of 20 months, disease free survival (DFS) and overall survival (OS) at 2 years were 36 and 38%, respectively. Major toxicity included myelosuppression and infection. Our experience demonstrates that a high dose of daunorubicin as liposomal compound can be safely administered in elderly ALL, exhibiting high antitumor activity. Our therapeutic program shows evidence of benefit in DFS and OS.

High functional P-glycoprotein activity is more often present in T-cell acute lymphoblastic leukaemic cells in adults than in children.

There is a distinct difference in prognosis between childhood versus adult acute lymphoblastic leukaemia (ALL). To define whether multidrug resistance (MDR) genes might contribute to this distinction, the expression and functional activity of P-glycoprotein (P-gp) and MDR associated proteins (MRP) were determined with RT-PCR (MDR-1, MRP1, MRP2, MRP3) and flow cytometry (P-gp and MRP). Patient samples were obtained from 36 children and 35 adults with de novo ALL. Of these patients, 38 showed a T-lineage and 33 showed a B-lineage immunophenotype. In the samples, large variability in P-gp activity (0.8-4.9) and MRP activity (1.1-13.9) was observed. Most T-ALL patients with high P-gp activity were adults (89%). The mRNA expression of MDR-1 correlated weakly with P-gp activity. In contrast, MRP activity did not correlate with the mRNA expression of MRP1, MRP2 and MRP3. In T-ALL, a worse overall survival and event-free survival was observed with increasing P-gp activity. P-gp activity had no prognostic impact in B-lineage ALL. In addition, high MRP activity did not influence treatment outcome in either T- or B-lineage ALL. Multivariate Cox regression analysis, showed P-gp activity to be the only unfavourable prognostic factor for overall survival in T-ALL. In conclusion, this study demonstrates the prognostic relevance of P-gp activity in T-ALL. Since the majority of the patients with high P-gp activity were adults, P-gp might contribute to the poor prognosis of adult T-ALL.

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.