Giuseppe Todeschini

Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years' experience of infection in GIMEMA centres

Summary. 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‐Hodgkins 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.

Serum levels of soluble CD30 are elevated in the majority of untreated patients with Hodgkin's disease and correlate with clinical features and prognosis.

PURPOSE To evaluate the serum levels of the soluble form of the CD30 molecule (sCD30) in patients with Hodgkins disease (HD) to establish whether there is a correlation with clinical features at presentation and prognosis. PATIENTS AND METHODS The sCD30 serum levels of 117 patients were measured at diagnosis with a commercial sandwich enzyme-linked immunoadsorbent assay (ELISA) test kit, and in 78 of these patients the sCD30 levels were also recorded during the follow-up period. RESULTS sCD30 levels at diagnosis were increased (> 20 U/mL) in a high proportion of patients (87.2%; mean +/- SD, 108 +/- 134 v 5.3 +/- 5.7 U/mL in controls, P < .0001) and correlated with stage (stages I + II, 73 +/- 97 U/mL; III + IV, 162 +/- 165 U/mL; P < .0001), with presence of B symptoms (stage A, 69 +/- 82 U/mL; stage B, 162 +/- 171 U/mL; P < .0001), and, to some extent, with tumor burden (bulky presentation, 141 +/- 129 U/mL; nonbulky, 91 +/- 133 U/mL; P = .058). Patients with sCD30 levels greater than 100 U/mL at diagnosis had a significantly higher rate of poor outcome in terms of failure to achieve a complete remission (CR) or disease relapse after CR achievement. In fact, the event-free survival (EFS) duration of patients with sCD30 levels greater than 100 U/mL was significantly worse (P = .0016). Using multivariate analysis, an sCD30 level greater than 100 U/mL retained its significance after adjustment for other prognostic parameters. CONCLUSION sCD30 in HD at presentation strictly correlates with clinical features. Serum levels greater than 100 U/mL at diagnosis entail a significantly higher risk of treatment failure, a factor that is independent of other prognostic parameters.

Mediastinal large-B-cell lymphoma with sclerosis: a clinical study of 21 patients.

We report the clinical findings of 21 consecutive patients affected by mediastinal large B-cell lymphoma with sclerosis. This type of lymphoma is a recently described histopathologic entity characterized on clinical grounds by distinctive features, which, according to our series, can be summarized as follows: young age (median, 30 years; range, 15 to 42 years), prevalence of females over males (15 v six), rare occurrence of superficial lymph node enlargement (three of 21 patients), and involvement of unusual extranodal sites (kidney six, adrenal cortex two patients). The clinical course appears to be closely related to treatment. In fact, complete remission (CR) was not obtained in the six patients submitted to conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus bleomycin (CHOP-Bleo) regimens until 1985, as opposed to 13 CRs reached in the 15 patients subsequently treated with more aggressive regimens after 1985 (methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B], 12 patients; methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone [M-BACOD], two patients; and vincristine, cyclophosphamide, fluorouracil, cytarabine, doxorubicin, methotrexate, and prednisone [F-MACHOP], one patient; plus involved-field radiotherapy, 10 patients). Among the 13 patients who achieved a CR, only one relapse was observed at 10 months. The median overall survival of complete responders after an observation period of 11 to 69 months has not yet been reached, and the event-free survival curve indicates that 90% of patients who achieve CR may be potentially cured.

Serum levels of the soluble form of CD30 molecule as a tumor marker in CD30+ anaplastic large-cell lymphoma.

PURPOSE To determine serum levels of the soluble form of CD30 molecule (sCD30) in patients with Ki-1/CD30+ anaplastic large-cell lymphoma (ALCL), and to evaluate its correlation with clinical features at presentation and its possible role as a tumor marker to monitor response to treatment and subsequent follow-up. PATIENTS AND METHODS sCD30 serum levels were measured with an improved commercial sandwich enzyme-linked immunosorbent assay (ELISA) test kit in 24 patients with CD30+ ALCL at diagnosis and in 13 after treatment. RESULTS Increased values (> 20 U/mL) at diagnosis were observed in 23 of 24 cases (median, 842.5 U/mL; range, 16 to 37,250) as compared with controls (P < .0001). These values were greater than those of 60 stage-matched cases of Hodgkins disease (HD) (P < .0001). The highest median value was observed in patients with T-cell-type ALCL (1,690 U/mL), with a significant overall difference as compared with B- and null-cell types (P = .004). Phenotype maintained its significance when results were corrected for other parameters, such as age, sex, and stage (P = .03). sCD30 values returned to the normal range in complete remission (CR), but remained increased in one patient who only partially responded to treatment. Subsequent increases of sCD30 levels were recorded in four of four patients after relapse. CONCLUSION sCD30 appears to be a new biologic serum tumor marker of possible use in the clinical setting of CD30+ ALCL.

Acute lymphoblastic leukaemia occurring as second malignancy : report of the GIMEMA Archive of Adult Acute Leukaemia

Between July 1992 and June 1996, 901 new cases of adult acute lymphoblastic leukaemia were recorded in the GIMEMA Archive of Adult Acute Leukaemia; 21 of them (2.3%) had a previous primary malignancy (PM). We found that secondary acute lymphoblastic leukaemia cases (sALL) presented with older age, a high incidence of pre‐pre‐B immunophenotype and a significantly higher prevalence of cancer among relatives compared to de novo ALL.

Oral itraconazole plus nasal amphotericin B for prophylaxis of invasive aspergillosis in patients with hematological malignancies

The use of oral itraconazole (200 mg daily) plus nasal amphotericin B (10 mg daily) for prophylaxis of invasive aspergillosis was evaluated in 164 patients with hematological malignancies at risk due to presence of neutropenia and/or steroid therapy. This prophylactic regimen was evaluated for a period of two years. Two hundred and ninety patients with similar characteristics who were observed over the three-year period prior to the introduction of prophylaxis served as historical control group. Environmental surveillance during the study period showed constant contamination of the air withAspergillus. Prophylaxis significantly reduced the incidence of proven invasive aspergillosis from 12/290 to 0/164 (p=0.004), and reduced the mortality rate from 8/290 to 0/164. The incidence of proven plus probable aspergillosis amounted to 34/290 in the control group and 8/164 in the study group (p=0.01); the mortality rates were 11/290 (3.7 %) and 2/164 (1.2 %) respectively. All nasal cultures in the study group were negative forAspergillus. The prophylactic regimen was well tolerated. Larger studies assessing each agent alone and in combination are necessary to confirm these observations.

Molecular features of primary mediastinal B-cell lymphoma: involvement of p16INK4A, p53 and c-myc

Primary mediastinal B‐cell lymphoma (PMBL) shows chromosome 9p anomalies in 50% of cases. Based on reports that p16INK4A gene, located on this chromosomal arm, is frequently altered in aggressive lymphomas, we analysed for alterations of this gene in 27 cases of PMBL, which were part of a series of 32 PMBL cases that have been characterized for alterations in c‐myc, p53, N‐ras, bcl‐1, bcl‐2, bcl‐6 and for Epstein‐Barr virus (EBV) infection. Four cases showed p16INK4A gene anomalies, including three with promoter methylation and one homozygous deletion. Eight PMBLs showed c‐myc rearrangements. Three additional cases showed sequence variations in the c‐myc P2 promoter, two of which consisted of the same germline variation involving a novel polymorphic XhoI site. Four tumours contained p53 gene mutations and three had clonal EBV infection. One case had a bcl‐6 rearrangement. In conclusion, our study shows that p16INK4, c‐myc and p53 alterations occur in 15%, 25% and 13% of PMBLs, respectively. EBV monoclonality was found in 9% of cases, whereas no abnormality was detected in bcl‐1, bcl‐2 and N‐ras. Thus, none of the common genetic aberrations seen in other types of non‐Hodgkins lymphomas appears to be stringently involved in the pathogenesis of this unique lymphoma type.

Serum levels of soluble interleukin‐2 receptor in hairy cell leukaemia: a reliable marker of neoplastic bulk

In hairy cell leukaemia (HCL), the strong membrane expression of the Tac antigen, corresponding to the p55 chain of the interleukin‐2 receptor (IL‐2R), is associated with the presence in the serum of high levels of a soluble form of the same molecule (sIL‐2R). Previous observations that therapy‐induced clinical and haematologic improvement in HCL is accompanied by a progressive decrease of sIL‐2R suggest a possible correlation between sIL‐2R levels and tumour burden. To verify this hypothesis, we monitored the variation of sIL‐2R values in 13 non‐splenectomized HCL patients admitted for treatment with recombinant interferon alpha‐2. The data were correlated with the estimated weight of bone marrow (BM) and spleen infiltrations, which in these patients almost entirely account for the tumour mass. The regression analysis test showed a direct correlation between sIL‐2R values and both BM neoplastic involvement (r= 0.63) and spleen tumour mass (r= 0.76). In addition, the correlation was further improved (r= 0.86) when sIL‐2R values were correlated with the total neoplastic mass, as calculated by the sum of spleen and BM neoplastic tissue weight. These data indicate that the detection of sIL‐2R in HCL is a reliable non‐invasive marker of tumour burden, which can be regarded as an additional useful tool for monitoring treatment response.

Improved prognosis of Pseudomonas aeruginosca bacteremia in 127 consecutive neutropenic patients with hematologic malignancies

OBJECTIVES Although decreasing in frequency, Pseudomonas aeruginosa bacteremia is still a major challenge for neutropenic cancer patients. In patients with hematologic malignancies, the prognosis of P. aeruginosa bacteremia is particularly poor due to the prolonged and severe neutropenia, mucosal damage, and other defects in immunity related both to the underlying disease and to the cytotoxic therapy. METHODS To verify the outcome of P. aeruginosa bacteremia and to try to define possible prognostic factors, the authors reviewed the medical records of 127 consecutive episodes of P. aeruginosa bacteremia observed in the hematologic unit of the Verona University School of Medicine. RESULTS Presence of pneumonia and septic shock, persistence and severity of neutropenia, delayed and inappropriate antibiotic therapy, and unresponsive underlying disease had negative impact on clinical outcome of P. aeruginosa bacteremia. CONCLUSIONS With recognition of the risk factors and more careful management, the prognosis of P. aeruginosa bacteremia in neutropenic patients with hematologic malignancies has improved in recent years.

Intensive short-term chemotherapy regimen induces high remission rate (over 90%) and event-free survival both in children and adult patients with advanced sporadic Burkitt lymphoma/leukemia.

The optimal treatment of advanced sporadic Burkitt lymphoma in adults is still a matter of debate. The salutary results of pediatric therapies did open the road for improving the adult outcome. Between May 1988 and March 2009, 71 consecutive patients—46 adults, 25 children—affected by Burkitt lymphoma/leukemia were treated with the same intensive pediatric protocol alternating vincristine, adriamycine and fractionated ciclophosphamide (phase A) with high dose methotrexate and high dose cytarabine (phase B) in four Italian institutions. Eighty‐nine per cent of patients were in Stage III–IV or had L3 leukemia. Complete remissions were 67/71 (94.4%), 24/25 (96%) in children, and 43/46 (93.5%) in adults. Toxic deaths were 3/71 (4.2%), all in adults. There were nine relapses (one in children, eight in adults), all but one observed early. After a median observation of 94 months (range 23–275), the Event–Free Survival rate is 92% in children and 71.7% in adults (P = 0.067). The 23 more recent adults received also rituximab, without differences in outcome as compared to patients who did not. Our experience confirms that such an intensive pediatric‐derived chemotherapy is feasible and improves the long‐term outcome of adults with advanced Burkitt lymphoma. Am. J. Hematol., 2012.