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Background: Childhood anaplastic large cell lymphoma (ALCL) is a well defined entity with a rather poor prognosis. Different approaches have been adopted in the treatment of ALCL in various cooperative trials, including short high-dose intensive therapy and leukemia-like protocols. In the early 1990s, the Italian Association of Pediatric Hematology and Oncology (AIEOP) initiated a multicenter trial for the treatment of ALCL based on a modified LSA2-L2 protocol., Methods: Thirty-four consecutive eligible children with newly diagnosed ALCL were enrolled in the AIEOP LNH-92 protocol. Treatment was comprised of an induction of remission phase, followed by consolidation and maintenance for a total duration of 24 months, independently of disease stage., Results: Thirty of 34 patients (88%) achieved complete disease remission and 8 patients experienced disease recurrence. With a median follow-up of 8.4 years, the probabilities of survival and event-free survival were 85% (range, 79-91%) and 65% (range, 57-73%), respectively. Therapy was well tolerated and hematologic toxicity was the most frequent toxicity., Conclusions: The leukemia-like protocol AIEOP LNH-92 was found to be an effective treatment for childhood ALCL. Its long duration may be beneficial to specific patient subgroups, but optimal treatment duration in ALCL remains to be elucidated., (Copyright 2005 American Cancer Society)

Perforin mutations have been demonstrated in a proportion of patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH). In the present study, we evaluated whether some patients with lymphoma sharing clinical characteristics with HLH might harbor mutations of the perforin gene. We analyzed 29 patients and found that 4 patients, who developed either Hodgkin or non-Hodgkin lymphoma, had biallelic mutations of the perforin gene. One of these 4 patients, a 19-year-old female with T-cell lymphoma, had a brother carrying the same mutations who developed HLH. In 2 of the 4 patients with biallelic mutations of the perforin gene, we evaluated perforin expression by flow cytometry and natural killer (NK) activity and both were found to be absent. Moreover, we documented the presence of monoallelic mutations of the perforin gene in 4 more patients. One of these 4 latter patients also carried a mutation of the Fas gene. These data indicate that perforin deficiency, either alone or in combination with other mutations of genes involved in lymphocyte survival or functional activity, may be present in patients with lymphoma. These findings suggest that perforin also plays a key role in the mechanisms of immune surveillance that prevent tumor growth and/or development.

Seventy-three children with acute lymphoblastic leukaemia (ALL) in first bone marrow (BM) relapse, occurring within 30 months from complete remission (CR), were enrolled in an Italian cooperative study (ALL R-87 protocol). This treatment programme consisted of an induction phase with intermediate-dose cytarabine (IDARA-C) plus idarubicin (IDA) and prednisone (PDN), followed by a multidrug consolidation therapy and bone marrow transplant (BMT). 55/73 children achieved CR (75.3%); 15 (20.5%) failed to respond and three (4.2%) died during induction. The response rate was significantly higher for children with a first CR duration > or = 12 months (P=0.0005) and for those with a white blood cell (WBC) count at relapse < 20 x 10(9)/l (P=0.004). The estimated disease-free survival (DFS +/- SE) at 82 months was 0.18 +/- 0.05 for all responders, and 0.70 +/- 0.14 for allotransplanted patients versus 0.05 +/- 0.05 for those autografted (P=0.001). The estimated probabilities of survival +/- SE and event-free survival (EFS +/- SE) at 83 months were 0.16 +/- 0.07 and 0.13 +/- 0.04, respectively. for all enrolled children. Univariate analysis showed that age < 10 years at initial diagnosis and B-lineage immunophenotype favourably influenced both DFS (P=0.001) and EFS probabilities (P=0.0014 and P=0.012, respectively), whereas a first CR duration > or = 12 months and a WBC count at relapse < 20 x 10(9)/l were associated only with a better EFS rate (P=0.026 and P=0.004, respectively). Our results show the efficacy of the IDA plus IDARA-C schedule used in the ALL R-87 protocol in high-risk relapsed ALL children. Allogeneic BMT proved effective for patients with an HLA sibling donor. In a multivariate analysis, age > or = 10 years at initial diagnosis (P=0.016) and WBC count at relapse > or = 20 x 10(9)/l (P=0.048) were independently associated with a worse disease outcome.

In children with immune thrombocytopenic purpura (ITP), bone marrow lymphocytes can express the common acute lymphoblastic leukemia antigen (CALLA) pattern with no evidence of leukemia or lymphoma. Bone marrow lymphocytes from 23 children and 20 adults affected with ITP were studied to determine the incidence and the clinical impact of lymphocytes with the immature B-cell phenotype and CD34+ cell expression. In this investigation we identified a group consisting of 52% of the children who showed the immature B phenotype, while the remaining 48%, similarly to adult ITP displayed an increase of T-cell antigens. CD34 was positive in 53% of children, but it was present in only half of the patients with the immature B phenotype and it was always absent in adults. IgH genes disclosed a germline configuration in all six patients in the immature B phenotype group. No difference was found in the two groups of children in terms of age, presentation of the disease or final outcome. Finally, no patient in either children's group has developed an acute lymphoproliferative disorder.

In vitro stimulation of peripheral blood lymphocytes from ten patients with chronic lymphocytic leukaemia (CLL) was investigated under various culture conditions. It was confirmed that the mitogenic reactivity of whole cell populations (PBL) was delayed and depressed. When CLL rosette-forming cells (RFC) were stimulated, their 3H-thymidine uptake was increased, but the pattern of the response was similar to that of whole PBL, thus suggesting some impairment of these cells. Furthermore, in order to evaluate the possible recruitment of B cells, generally thought to be unresponsive, some co-culture experiments were performed in which 10(4) normal lymphocytes and 10(5) CLL whole PBL or RFC-depleted cell populations were stimulated with mitogens. An amplified response of the CLL lymphocytes was obtained in all co-cultures, and this effect was more evident when specific T cell stimulants were used; autologous CLL T lymphocytes, on the contrary, failed to display such a 'synergic' effect. These results indicate that normal lymphocytes are able to recruit a large number of CLL lymphocytes in the mitogenic response; furthermore, the fact that in co-cultures of CLL T-depleted fractions a better response was obtained with T cell mitogens suggests that the definition of CLL as a clonal expansion of unresponsive 'B' lymphocytes may be inadequate.

Based on conventional and immunological cell markers the great majority of acute leukemias can be classified as of lymphoid or myeloid origin. However, in some instances, leukemic cells with both lymphoid and myeloid features are found. For these cases the term of hybrid leukemia has been suggested; moreover, it has been shown that dual markers can be expressed by the same cell (biphenotypic leukemia) or myeloid and lymphoid cell populations coexist (biclonal leukemia). The accurate typing of acute leukemia is crucial in order to entail treatment and predict survival; therefore, the identification of acute hybrid leukemias may be important not only in terms of biological significance but also of management and outcome. We report here two further cases of acute hybrid leukemia with poor response to chemotherapy and very short survival.

T-lymphocyte colony formation in agar culture was investigated in 20 untreated B-cell Chronic Lymphocytic Leukemia (CLL) patients in stage O. As compared to the controls, colony growth was very poor when unseparated peripheral-blood lymphocytes from CLL-patients were seeded. The number of colonies was greatly higher when T-cell enriched fractions from CLL were plated; however, they failed to reach the normal range even in this experimental condition. The role of adherent cells in the colony growth was also investigated. Depletion of these cells resulted in impaired colony generation either in normals or in CLL-patients, which was subsequently restored by the addition of the same adherent cells. In the patients investigated in this study, an imbalance of T-subsets was found with increase of OKT8-positive cells (T-suppressors). When the number of colonies and the percentage of OKT8-positive cells were plotted, an inverse correlation was found. Conversely, a linear relationship was detected between the percentage of OKT4-positive cells (T-helpers) and the values of colonies. On the basis of the present experiments, it is suggested that the defective colony growth of T-cell fractions in B-cell CLL may be related to the low number of OKT4-positive cells plated, which are known to be mainly responsible for the colony generation in agar culture.

The peripheral blood lymphocytes of 13 previously untreated chronic lymphocytic leukemia (CLL) patients showed a decreased and delayed response in vitro to plant mitogens (PHA and PWM) and specific antigens (PPD and MLC). In addition, the serum of these patients inhibited the mitotic reactivity of both autologous and homologous normal lymphocytes. Since incubation with CLL serum did not affect the SRBC-rosetting capacity of normal lymphocytes, we believe that CLL serum interferes with some metabolic stage in blastogenesis rather than at the level of mitogen membrane interaction. The in vitro transformation of lymph node, bone marrow and peripheral blood lymphocytes in some of these patients was also investigated. Stimulation of peripheral blood cells with plant mitogens resulted in a more serious impairment of the response than that found with bone marrow and lymph node cells. This could be explained by the fact that, although CLL is a widespread lymphoproliferative disorder, some preferential homing of normally reactive cells in the bone marrow and lymph nodes cannot be excluded. Finally, since no stimulation was observed in mixed leukocyte cultures (MLC), our experiments provide evidence that no antigenic differences are detectable in CLL lymphoid populations.