Peripheral T-cell lymphomas (PTCLs) receiving conventional treatment have a poor clinical outcome. We conducted a phase II study to evaluate the feasibility and efficacy of chemo-immunotherapy in young (⩽60 years old, Clin A study) and elderly (>60 and ⩽75 years old, Clin B study) patients with newly diagnosed PTCL. Clin A patients (n=61) received two courses of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone)-21 with alemtuzumab (AL, 30 mg) followed by two courses of high-dose chemotherapy. On the basis of donor availability, patients in response received allogeneic (allo) or autologous (auto) stem cell transplantation (SCT). Clin B patients (n=25) received six courses of CHOP-21 and AL (10 mg). Clin A responding patients were 38 of 61 (62%) and received alloSCT (n=23) or autoSCT (n=14); one complete remission (CR) patient was not transplanted. At a median follow-up of 40 months, the 4-year overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) rates were 49, 44 and 65%, respectively. In Clin B study, the response rate was 72%. At a median follow-up of 48 months, the 4-year OS, PFS and DFS rates were 31, 26 and 44%, respectively. In conclusion, front-line alloSCT or autoSCT is effective in prolonging DFS in young patients; AL in elderly improved response with no survival benefit.

OBJECTIVETo evaluate the clinical characteristics and outcome of NK/T-cell lymphoma 'nasal type' developed in Italian patients.PATIENTSBetween 1997 and 2004, 26 new cases of NK/T-cell lymphoma 'nasal type' were diagnosed in 10 Italian Hematology institutions.RESULTSAll patients were Caucasian, male/female ratio was 19/7, with a median age of 50 years (range 20-80). In 23 cases presentation at the onset was in the nasal cavity or adjacent structures, in two cases the lymphoma onset with skin lesions was followed successively by rhynopharyngeal dissemination, while the remaining case had bone marrow and lymph node involvement followed by oro-pharyngeal involvement. Regarding the stage of disease: 12 patients were in stage I; six in stage II; eight in stage IV. Diagnosis was based on the finding of a NK/T-cell phenotype at the histological and immunophenotypic examination of oropharyngeal or cutaneous lesions. All patients but one were treated with chemotherapy, alone in nine cases or associated to radiotherapy in 14 cases; two patients had chemotherapy, radiotherapy and surgery, while one patient underwent only surgery. Chemotherapy was anthracycline-based in 17 out of 25 cases. In those patients in whom radiotherapy was performed, radiation dosages ranged between 36 Gy and 47.5 Gy, with a median dosage of 40 Gy. Nine patients (34%) were responsive to the treatments: six patients obtained a complete remission and other three a partial remission. The remaining 17 patients resulted refractory or presented a limited response to therapy. The median disease-free survival was 14 months and the median overall survival time was 9 months.CONCLUSIONThe results of this retrospective survey confirmed that NK/T-cell lymphoma 'nasal type' is a very rare lymphoma in the Italian population, and it is characterized by a very bad prognosis. Due to the rarity of this disease, a standardized therapeutic approach is lacking. More data are needed to know the epidemiology of this kind of lymphoma in Europe.

AbstractBACKGROUNDPatients who have aggressive, refractory or recurrent non‐Hodgkin lymphomas (NHLs) that are refractory to first‐line anthracycline‐containing regimens (ACRs) have a dismal outcome. Achieving complete remission (CR) is essential for a favorable outcome. To improve the CR rate in these patients, the authors designed a new protocol that contained hyperfractionated cyclophosphamide (CTX), high‐dose arabinosylcytosine (HiDAC), and high‐dose methotrexate (MTX) delivered sequentially in the same cycle and followed by the administration of granulocyte‐colony stimulating factor (G‐CSF) (HyperCHiDAM Verona 897).METHODSBetween February 1998 and May 2002, 28 consecutive adult patients (median age, 44 years) with aggressive NHL (B‐lineage in 21%, T‐lineage in 7%, and Ki‐67 percentage > 50 in 82%) were entered on the protocol after they had failed on ACRs (15 patients with refractory disease, 6 patients with stable disease, 5 patients with recurrent disease, and 2 patients in partial remission). Patients characteristics were as follows: Twenty‐two patients had Stage III–IV NHL (78.6%), 19 patients had B symptoms (67.8%), 22 patients had extranodal disease (78.6%), 12 patients had bulky mass (42.8%), 18 patients elevated lactate dehydrogenase levels (66%), and 8 patients had high‐intermediate/high International Prognostic Index scores (64.3%). Patients received hyperfractionated CTX (300 mg/m2) and HiDAC (2 g/m2) every 12 hours on Days 2–4 and received high‐dose MTX (400 mg/m2 bolus plus 1600 mg/m2 as a 24‐hour continuous infusion on Day 1 with folinic rescue), followed by G‐CSF. Subsequently, 15 patients underwent autologous stem cell transplantation (SCT), and 4 patients underwent allogeneic SCT.RESULTSA CR was achieved by 18 of 28 patients (64.3%), a partial remission was achieved by 6 patients (21.4%), 4 patients were nonresponders or had progressive disease (14.3%), and there was 1 early toxic death (3.5%). Two of 18 patients developed recurrent disease (11.1%). The median follow‐up for all patients was 35 months (range, from 2 months to ≥ 74 months). Among the patients who achieved a continuous CR, the median follow‐up was 48 months (range, from ≥ 32 months to ≥ 73 months). At the time of the current report, 13 of 28 patients (46.42%) were event‐free.CONCLUSIONSHyperCHiDAM Verona 897 was an effective regimen for patients with aggressive NHL who failed on ACRs, and it allowed patients to undergo subsequent SCT. Cancer 2005. © 2005 American Cancer Society.

The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 0496 protocol, through the central handling of bone marrow samples at presentation, allowed us to combine cytogenetic and molecular information on a large series of adults with acute lymphoblastic leukemia (ALL) treated homogeneously, enabling us to define as broadly as possible their genetic profile and to determine the impact on outcome of the cytogenetic-molecular signature. Of 414 patients centrally processed, 325 were considered for the categorization into the following cytogenetic-molecular subgroups: normal, t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1;19)/E2A-PBX1, 9p/p15-p16 deletions, 6q deletions, miscellaneous structural abnormalities, and hyperdiploid. The inclusion into each subgroup was based on a hierarchical approach: molecular abnormalities with adverse prognosis had precedence over karyotypic changes with less-defined prognosis and the latter over ploidy. Patients without abnormalities and those with isolated 9p/p15-p16 deletions showed a relatively favorable outcome (median disease-free survival [DFS], > 3 years). The t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1; 19)/E2A-PBX1 defined a group with dismal prognosis (median DFS, 7 months), whereas 6q deletions, miscellaneous aberrations, and hyperdiploidy predicted an intermediate prognosis (median DFS, 19 months). This study highlights the importance of a combined cytogenetic-molecular profiling of adult ALL at presentation as a critical independent determinant of their outcome, providing further evidence of the necessity of a risk-adapted therapeutic algorithm for an optimal management of these patients.

The optimal treatment of primary mediastinal large B-cell lymphoma (PMLBCL) is still undefined. In the absence of randomised studies, we retrospectively analysed: (a) the effectiveness of two chemotherapy regimens (CHOP vs MACOP-B/VACOP-B) in complete remission (CR) achievement and event-free survival (EFS) and (b) the role of mediastinal involved-field radiotherapy (IF-RT) as consolidation. From 1982 to 1999, 138 consecutive patients affected by PMLBCL were treated in 13 Italian institutions with CHOP (43) or MACOP-B/VACOP-B (95). The two groups of patients were similar as regard to age, gender, presence of bulky mediastinal mass, pleural effusion, stage and international prognostic indexes category of risk. Overall, 75.5% of patients in CR received IF-RT as consolidation. Complete remission was 51.1% in the CHOP group and 80% in MACOP-B/VACOP-B (P<0.001). Relapse occurred in 22.7% of CHOP- and in 9.2% of MACOP-B/VACOP-B-treated patients (n.s.). Event-free patients were 39.5% in CHOP and 75.7% in the MACOP-B/VACOP-B group (P<0.001). The addition of IF-RT as consolidation improved the outcome, irrespectively of the type of chemotherapy (P=0.04). At a multivariate analysis, achievement of CR (P<0.0001) and type of CT (MACOP-B/VACOP-B) retained the significance for OS (P=0.008) and EFS (P=0.03). In our experience, MACOP-B/VACOP-B appears to positively influence OS and EFS in patients affected by PMLBCL, as compared to CHOP. Consolidation IF-RT on mediastinum further improves the outcome of CR patients.

To assess the prognosis of peripheral T-cell lymphoma unspecified, we retrospectively analyzed 385 cases fulfilling the criteria defined by the World Health Organization classification. Factors associated with a worse overall survival (OS) in a univariate analysis were age older than 60 years (P=.0002), equal to or more than 2 extranodal sites (P=.0002), lactic dehydrogenase (LDH) value at normal levels or above (P<.0001), performance status (PS) equal to or more than 2 (P< or =.0001), stage III or higher (P=.0001), and bone marrow involvement (P=.0001). Multivariate analysis showed that age (relative risk, 1.732; 95% CI, 1.300-2.309; P<.0001), PS (relative risk, 1.719; 95% CI, 1.269-2.327, P<.0001), LDH level (relative risk, 1.905; 95% CI, 1.415-2.564; P<.0001), and bone marrow involvement (relative risk, 1.454; 95% CI, 1.045-2.023; P=.026) were factors independently predictive for survival. Using these 4 variables we constructed a new prognostic model that singled out 4 groups at different risk: group 1, no adverse factors, with 5-year and 10-year OS of 62.3% and 54.9%, respectively; group 2, one factor, with a 5-year and 10-year OS of 52.9% and 38.8%, respectively; group 3, 2 factors, with 5-year and 10-year OS of 32.9% and 18.0%, respectively; group 4, 3 or 4 factors, with a 5-year and 10-year OS of 18.3 and 12.6%, respectively (P< or =.0001; log-rank, 66.79).

We have read with interest the comment by Todeschini et al. [1], focusing on the best treatment for aggressive non-Hodgkin’s lymphoma (NHL) in elderly patients: rituximabCHOP (R-CHOP) or 2-weekly CHOP þ G-CSF (CHOP-14). We agree with the authors that the two studies by Coiffier et al. [2] and Pfreundschuh et al. [3] represent important new achievements in the treatment of non-Hodgkin’s lymphoma in elderly patients, but we think that there are some issues that should be raised. In our opinion, the best arguments for the use of R-CHOP for aggressive lymphomas in elderly patients come from one well-designed randomized phase III trial, which represents level 1 evidence according to ASCO guidelines [2], positive data from unplanned subgroup analysis of a phase III trial, i.e. level 2 evidence [4], positive data from one pre-post study, i.e. level 3 evidence [5], and positive data from a panel of experts [6]. Overall, evidence tends to show that R-CHOP is superior to CHOP in elderly patients with diffuse large B-cell lymphomas in terms of response, event-free survival and overall survival, with no significant increase in toxicity. Based on this evidence, some countries have decided to consider RCHOP as standard treatment, even if it appears difficult to consider R-CHOP as standard until a confirmation trial is published. The data in favor of CHOP-14 are based only on one trial that, so far, has been repeatedly published only in an abstract form, with very few data on toxicity. We are waiting for the full paper to be published. Therefore, we think that it is too early to state that CHOP-14 can be considered a standard treatment. Nevertheless, some European groups, like HOVON and DSHNHL, chose CHOP-14 as a standard arm for their trials. In fact, a study from the Dutch group HOVON is ongoing, aimed at assessing in a randomized comparison the efficacy of rituximab combined with 2-weekly CHOP þ GCSF versus 2-weekly CHOP þ G-CSF alone in patients older than 65 years, while the RICOVER-60 study by the DSHNHL is comparing CHOP-14 (six or eight cycles) þ rituximab versus CHOP-14 (six or eight cycles) alone in patients aged 61– 80 years. The results of these trials are also eagerly awaited. On the other hand, we believe that a Comprehensive Geriatric Assessment (CGA) is crucial in the evaluation of this type of patient, and we strongly recommend that treatment should be CGA-driven, as we recently proposed in a new approach for elderly patients affected by NHL, allowing a patient-tailored treatment with the goal of maintaining a balance between the desire to cure the patient and guaranteeing a good quality of life [7]. This approach, based on a CGA including the ADL and IADL scales, is suitable and highly effective and it does not exclude any elderly patient from potentially curative chemotherapy. The value of CGA is also being prospectively investigated by the EORTC in two phase-II studies in elderly fit (EORTC protocol 20991) and frail (EORTC protocol 20992) patients. D. Bernardi*, A. Giacalone, M. Spina & U. Tirelli

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily exerting cytotoxic activities toward tumor cells. Herein, we demonstrate that therapeutic concentrations of interferon alpha (IFNalpha) stimulate the expression of high levels of TRAIL mRNA and the release of elevated amounts of a soluble bioactive form of TRAIL (sTRAIL) in both human neutrophils and monocytes. Supernatants harvested from IFNalpha-treated neutrophils/monocytes elicited, on TRAIL-sensitive leukemic cell lines, proapoptotic activities that were significantly reduced by either a combination of TRAIL-R1/Fc and TRAIL-R2/Fc chimeras or neutralizing anti-TRAIL, anti-TRAIL-R1, and anti-TRAIL-R2 antibodies, suggesting that they were mediated by released sTRAIL acting on both TRAIL receptors. Since diseases such as chronic myeloid leukemia (CML) and melanoma are effectively treated with IFNalpha,we also demonstrate that CML neutrophils and peripheral blood mononuclear cells (PBMCs) cultured with IFNalpha at therapeutic concentrations retain the capacity of releasing sTRAIL, suggesting that CML leukocytes, in vivo, might represent an important source of sTRAIL. In this regard, we show that sTRAIL serum levels as well as leukocyte-associated TRAIL significantly increase in melanoma patients following IFNalpha administration. Collectively, these findings indicate that sTRAIL released by IFNalpha-activated neutrophils and monocytes contributes not only to the immunoregulatory actions but also to the therapeutic activities of IFNalpha.

Flow-cytometric detection of minimal residual disease (MRD) identifies patients with high relapse risk in childhood acute lymphoblastic leukaemia (ALL). We studied the efficacy of this method in adult T-ALL treated with the Italian co-operative GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) LAL0496 protocol. Bone marrow samples from 53 patients were taken at fixed treatment time points and MRD was analysed using a leukaemia-specific immunophenotype (cytoplasmic-CD3/nuclear-terminal desoxynucleotidyl transferase). The median follow-up was 17 months (range 3-61) and a median of 4.5 analyses/patient was performed (range 3-12). Six out of 53 (11.3%) patients were refractory to treatment, 30/53 (56.6%) relapsed and 17/53 (32.1%) remain in continuous complete remission. The probability of relapse at 2 years for MRD-positive patients at preconsolidation was 81.5%vs 38.9% for MRD-negative patients (P = 0.00078). This risk was still 54.5% for MRD-positive vs 15.8% for MRD-negative patients pre-third reinduction (P = 0.0098) and 50.0% for MRD-positive vs 16.4% for MRD-negative patients pre-sixth reinduction (P = 0.032). The relapse-predicting value of MRD did not depend on features at diagnosis such as age, sex and leucocyte count. Our data suggest that immunophenotypic MRD monitoring in the first year of treatment is a useful outcome predictor for adult T-ALL patients.

A retrospective survey was conducted over a 10-year period (1990-99) among 52 haematology divisions in order to evaluate the clinical and laboratory characteristics and outcome of patients with proven Pneumocystis carinii pneumonia (PCP) complicating haematological diseases. The study included 55 patients (18 with non-Hodgkin's lymphoma, 10 with acute lymphoblastic leukaemia, eight with acute myeloid leukaemia, five with chronic myeloid leukaemia, four with chronic lymphocytic leukaemia, four with multiple myeloma, three with myelodysplastic syndrome, two with myelofibrosis and one with thalassemia) who developed PCP. Among these, 18 (33%) underwent stem cell transplantation; only two received an oral prophylaxis with trimethroprim/sulphamethoxazole. Twelve patients (22%) developed PCP despite protective isolation in a laminar airflow room. The most frequent symptoms were: fever (86%), dyspnoea (78%), non-productive cough (71%), thoracic pain (14%) and chills (5%); a severe hypoxaemia was present in 39 patients (71%). Chest radiography or computerized tomography showed interstitial infiltrates in 34 patients (62%), alveolar infiltrates in 12 patients (22%), and alveolar-interstitial infiltrates in nine patients (16%). Bronchoalveolar lavage was diagnostic in 47/48 patients, induced sputum in 9/18 patients and lung biopsy in 3/8 patients. The diagnosis was made in two patients at autopsy. All patients except one started a specific treatment (52 patients trimethroprim/sulphamethoxazole, one pentamidine and one dapsone). Sixteen patients (29%) died of PCP within 30 d of diagnosis. Multivariate analysis showed that prolonged steroid treatment (P < 0.006) and a radiological picture of diffuse lung involvement (P < 0.003) were negative diagnostic factors.

The persistence of minimal residual disease (MRD) following the induction of complete remission (CR) in patients with acute lymphoblastic leukemia (ALL) predicts a poor outcome in childhood, whereas fewer data are so far available in adults. 1-6 In the present study we investigated MRD in a single center series of 24 adult patients with ALL using a flow-cytometric approach based on the detection of leukemia-specific marker combinations.

INTRODUCTION:One hundred-and-six adult cases of acute lymphoblastic leukemia were prospectively investigated using a highly sensitive interphase fluorescence in situ hybridization assay which utilizes DNA probes that detect a double BCR/ABL fusion signal (D-FISH) in cells carrying the t(9;22) to evaluate the reliability and specificity of this method for the detection of the Ph translocation. The results were compared with those obtained in the same cases by conventional cytogenetics and by reverse-transcription polymerase chain reaction. MATERIALS AND METHODS:The study was performed using DNA probes that span the common breakpoints of the t(9;22) translocation and that detect a double BCR/ABL fusion in cells carrying this karyotypic anomaly, one on the abnormal chromosome 9 and one on the Ph chromosome. RESULTS:Interphase D-FISH detected a high number of rearranged cases (22/106) compared to conventional cytogenetics (15/106) and RT-PCR (21/106). CONCLUSION:Interphase D-FISH emerges as a reliable, fast and relatively inexpensive tool for the detection of BCR/ABL rearrangements in adult ALL patients at diagnosis. It has a sensitivity clearly higher than conventional karyotyping and it may prove also superior to that of RT-PCR in cases with unusual BCR/ABL breakpoints. Our results suggest that D-FISH might be considered as the initial test for the diagnosis of Ph+ adult ALL.

Many anthracyclines seem to be essential components of chemotherapy in adult ALL patients. The results of different studies suggest that 1. anthracyclines increase the probability of CR 2. complete response is obtained earlier with the use of high-dose anthracyclines 3. the optimal timing for anthracycline administration is probably the very early phase of the disease, because an earlier CR is a favorable prognostic indicator in ALL 4. high-dose DNM may be beneficial: given at high dosage in a dose-intensive way it can reduce the occurrence of relapse. There is evidence from randomized and nonrandomized studies that anthracyclines increase the CR rates when added to other classic components of ALL therapy. The dose and dose intensity of DNM during induction may influence duration of CR and long-term prognosis. Although anthracyclines in induction are only part of a complex program of therapy for adult ALL, the dose and dose intensity of anthracyclines may become important components of the armamentarium against this devastating disease.