A prospective survey of febrile events in hematological malignancies.

The Hema e-Chart prospectively collected data on febrile events (FEs) in hematological malignancy patients (HMs). The aim of the study was to assess the number, causes and outcome of HM-related FEs. Data were collected in a computerized registry that systematically approached the study and the evolution of FEs developing in a cohort of adult HMs who were admitted to 19 hematology departments in Italy from March 2007 to December 2008. A total of 869 FEs in 3,197 patients with newly diagnosed HMs were recorded. Fever of unidentified origin (FUO) was observed in 386 cases (44.4%). The other causes of FE were identified as noninfectious in 48 cases (5.5%) and infectious in 435 cases (50.1%). Bacteria were the most common cause of infectious FEs (301 cases), followed by fungi (95 cases), and viruses (7 cases). Mixed agents were isolated in 32 episodes. The attributable mortality rate was 6.7% (58 FEs). No deaths were observed in viral infection or in the noninfectious groups, while 25 deaths were due to FUO, 16 to bacterial infections, 14 to fungal infections, and three to mixed infections. The Hema e-Chart provided a complete system for the epidemiological study of infectious complications in HMs.

The role of high-dose therapy and autologous stem cell transplantation in patients with primary refractory Hodgkin's lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL).

GISL recently conducted an exhaustive survey of 1078 patients with Hodgkin's Lymphoma (HL) enrolled between 1988 and 2002 in different prospective trials. Treatment failure was observed in 82 out of 1078 patients; of these 82 patients with refractory HL, complete information was available for 72, who form the evaluable population of the present study. After the initial therapy failure, 51 patients were treated with conventional salvage chemotherapy (CC) (n = 24) or high-dose chemotherapy (HDC) (n = 27); 4-year overall survival (OS) was 81% in the HDC group versus 38% in the CC group (P = 0.019). The remaining 21 patients had rapidly progressive disease and died. After a median follow-up of 2.8 years, the projected OS for all 72 patients is 58 and 49% at 3 and 5 years, respectively. Age <45 years, the absence of systemic symptoms and a PS <1 predicted a significantly longer OS. Interestingly, the majority of patients with two or three negative prognostic factors did not receive potentially curative therapy. In conclusion, HDC seems to be a reasonable option for selected patients with refractory HL, although the majority of them did not receive a transplant. Finally, patients with a high-risk score had little chance of receiving potentially curative treatment.

Modulation of purine analogs- and chlorambucil-induced cytotoxicity by alpha-interferon and interleukin-2 in chronic lymphocytic leukemia.

The decrease in cell viability observed in vitro from the effect of chlorambucil (CLB), fludarabine (FAMP) and 2-chlorodeoxy-adenosine (CDA) on peripheral lymphocytes from 49 untreated CLL patients was investigated by the MTT colorimetric assay. The effects of recombinant-interleukin (r-IL)-2 and alpha-interferon (alpha-IFN) on drug-induced cell death were evaluated. r-IL-2 significantly increased in vitro resistance to CLB, while purine analog cytotoxicity was slightly reduced by the cytokine. The potential in vivo significance of r-IL-2, acting as a survival signal on CLB-induced cell death, is supported by the correlation between the lowest IL-2 serum levels, the highest in vitro sensitivity to CLB and a major clinical response after CLB treatment in six out of eight CLL patients. Using 25 samples, alpha-IFN enabled CLL cells to increase resistance to CLB, CDA and FAMP in 14, eight and seven samples, respectively; conversely, alpha-IFN showed a synergism with both CLB and FAMP in six samples and with CDA in four. These results correlate with immunoenzymatic assay data showing that alpha-IFN either up- or down-regulates tumor necrosis factor and IL-1 levels in supernatants of some CLL samples. Apparently, alpha-IFN plays a dual role in regulating drug-induced cell death, while IL-2 seems to solely favor cell survival in CLL.

Alpha 2-interferon in B-cell chronic lymphocytic leukemia: clinical response, serum cytokine levels, and immunophenotype modulation.

Fifteen patients with B-cell chronic lymphocytic leukemia (B-CLL) have been treated with alpha 2b-interferon (alpha IFN) for one year (3 mega units subcutaneously three times a week). The hematological response and the modulation of immunophenotype, serum levels of soluble interleukin-2 receptor (sIL-2R) and tumour necrosis factor (TNF) have been monitored. Hematologically 67% of cases were classified as responders, although no complete responses were observed; three cases progressed during treatment, and two patients showed stable disease. Both peripheral lymphocytes and CD24+ cell absolute number significantly decreased after twelve months of IFN treatment (40.7 +/- 17 x 10(9)/l versus 15.8 +/- 6 x 10(9)/l, mean values +/- sd, p < 0.01, and 30.4 +/- 5.5 x 10(9)/l versus 8.1 +/- 2.8 x 10(9)/l, p < 0.05, respectively), while CD24+ cell percentage did not change (72.1% +/- 4.6 versus 67.5% +/- 8.8, p not significant). In the majority of cases myelomonocytic markers (CD11c, CD14, CD11b) transitorily decreased during the treatment. Serum sIL-2R levels, elevated in all cases before IFN treatment, increased in responders. Serum TNF levels decreased in patients showing high values before the treatment. The explanation of these findings and their possible implication are discussed.

Anaplastic large cell lymphoma (CD30+/Ki-1+). Analysis of 35 cases followed at GISL centres.

Between January 1988 and June 1992, 35 patients with primary anaplastic large cell lymphoma (ALCL)CD30+ were referred to one of the institutions participating in GISL (Gruppo Italiano per lo Studio dei Linformi). 16 patients were treated with ProMACE-CytaBOM, two with MACOP-B, one with CHOP and one with LSA2-L2. As of November 1990, all newly diagnosed patients were treated with MOPP/EBV/CAD hybrid. 27 (77%) cases of ALCL CD30+ and 8 (23%) cases of Hodgkin's-related (HR) lymphoma CD30+ were diagnosed. Extranodal disease was present in 22 cases (63%), and 8 patients (23%) had primary bone marrow involvement. Twenty-three complete remissions (CR) (66%), six partial remissions (PR) (17%) and six no remissions (NR) (17%) were achieved with induction therapy. Results achieved with ProMACE-CytaBOM and MOPP/EBV/CAD hybrid were comparable. The overall response rate (CR+PR) was 85% for patients with classic ALCL CD30+ and 87% for those with HR lymphoma CD30+. The 3 year estimated overall survival rate was 66% and the 3 year relapse free survival rate was 65% for the entire group. The only significant favourable prognostic factor was the achievement of CR with initial therapy. Our findings suggest that ALCL (CD30+/Ki-1+) has a clinical outcome similar to aggressive non-Hodgkin's lymphoma (NHL). The use of an anthracycline-containing regimen will provide a change of cure in approximately 65% of cases.

Peripheral blood CD38 expression predicts survival in B-cell chronic lymphocytic leukemia.

CD38 expression was investigated in 161 untreated patients with B-cell chronic lymphocytic leukemia (B-CLL). A score system, devised ad hoc by integrating the percentage and the mean fluorescence intensity (MFI) values of CD38(+) cells, indicated that B-CLL patients with a CD38 score < or =3 are characterized by a significantly longer survival compared to those with a CD38 score >3 (P=0.0026). Thirty-seven percent of patients with a CD38 score < or =3 and 58% of those with a score >3 were dead at 10 years. Multivariate analysis indicates that only the CD38 score successfully predicts survival (P=0.0028), with an estimated 3.8-fold greater risk of death for those cases with CD38 score >3.

Childhood acute lymphoblastic leukemia immunophenotypes and their prognostic significance: experience of the IGCI-study in 389 children. International Society for Chemo-immunotherapy (IGCI-Vienna) Cooperative Group.

The prognostic significance of immunophenotype and other features including sex, age, anaemia, WBC, FAB type, and PAS staining were analysed in a group of 389 children newly diagnosed as acute lymphoblastic leukemia (ALL) and treated according to the BFM 1981/1983 protocol. The CR rate was higher (82-94%) in immunophenotypic subgroups defined as 'non-B' compared with B-ALL (54%). The probability of being in CCR at the end of follow up was 0.68 (median. observation, 3 years). Using the stepwise Cox regression analysis the following independent factors predictive of duration of CCR were selected (relative risk in brackets): 1. WBC (> 25G/1:< 25G/1 = 2.0, P = 0.0008), 2. age (> 10y:2-10y = 1.3, P = 0.04), 3. CALLA positivity (neg.:posit. = 2.4, P = 0.04), 4. CALLA within B-cell progenitor ALL (pre;preB,Calla-:Calla+ = 1.7, P = 0.007). T-ALL appeared to have a worse prognosis than U-ALL and B-progenitor derived ALL but it did not retain independent prognostic significance in multivariate analysis.

Non-Hodgkin's lymphoma associated with sickle cell disease: a case report.

A case of non-Hodgkin's lymphoma with leukemic spread in a patient affected with homozygous sickle cell disease is reported. This association has not been previously described. A correlation between the malignancy and the hemoglobinopathy could not be etiologically ascertained; therefore, an alternative explanation to a chance event cannot be offered.

Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays.

To better define the significance of proliferation centers (PCs), the morphological hallmark of chronic lymphocytic leukemia (CLL), lymph node biopsies taken from 183 patients were submitted to histopathologic and fluorescence in situ hybridization (FISH) studies using a 5-probe panel on tissue microarrays. Seventy-five cases (40.9%) with confluent PCs were classified as 'PCs-rich' and 108 cases (59.1%) with scattered PCs were classified as 'typical'. Complete FISH data were obtained in 101 cases (55.1%), 79 of which (78.2%) displayed at least one chromosomal aberration. The incidence of each aberration was: 13q- 36,7%, 14q32 translocations 30.8%, 11q- 24.7%, trisomy 12 19.5% and 17p- 15.6%. Five cases showed extra copies of the 14q32 region. The 'PCs-rich' group was associated with 17p-, 14q32/IgH translocation, +12, Ki-67>30%. The median survival from the time of tissue biopsy for PCs-rich and typical groups was 11 and 64 months, respectively (P=0.00001). The PCs-rich pattern was the only predictive factor of an inferior survival at multivariate analysis (P=0.022). These findings establish an association between cytogenetic profile and the amount of PC in CLL, and show that this histopathologic characteristic is of value for risk assessment in patients with clinically significant adenopathy.

High dose continuous chlorambucil vs intermittent chlorambucil plus prednisone for treatment of B-CLL--IGCI CLL-01 trial.

279 B-CLL patients entered randomized IGCI clinical trial to compare the remission rate and survival of high dose continuous chlorambucil (regimen A) vs intermittent chlorambucil plus prednisone (regimen B), and to assess the effect of early treatment on survival. Regimen A was significantly better for remission induction (p less than 0.001), and prolonged survival (p less than 0.01) in comparison to regimen B. More aggressive chemotherapy is associated with better response but requires close monitoring of both antineoplastic effect and haematological toxicity. Total tumor mass score (TTM) proved to be suitable for definition of both early, stable disease and the response to therapy because of its quantitative continuous character and its independence of bone marrow failure. This system is helpful for the detection of treatment toxicity and consequently enables safe monitoring of therapy. Although statistically significant difference has not yet been reached between the patients treated early and non treated patients the latter group seems to fare better.

Factors affecting the uptake of prenatal diagnosis for sickle cell disease.

Between 1979 and 1990, 170 couples at risk of having children with sickle cell disease, resident in the UK and with a continuing pregnancy, were referred for counselling at the University College Hospital Perinatal Centre. Approximately 50% of the couples, including those where one partner actually had sickle cell disease, requested prenatal diagnosis. This was requested in 82% of pregnancies when the mother was seen in the first trimester of pregnancy and in 49% when she was seen in the second trimester. More than 90% of referred couples who already had an affected child requested prenatal diagnosis. The type of sickle cell disease involved and ethnic group also influenced choice. These results show the importance of detecting and counselling couples at risk before pregnancy whenever possible.

Reduced natural killer cell activity in non-hodgkin's lymphoma.

Natural Killer (NK) activity is investigated in 20 patients with non-Hodgkin's Lymphoma (NHL) and in 20 healthy subjects. Peripheral blood lymphocytes are used as effector cells, and 51Cr labelled K562 myeloid cells as targets. Experiments are carried out either at effector/target ratio of 20:1 or 40:1, in 4 hrs Cr released assay. As compared to controls, a reduced NK activity is found in NHL patients, but that difference is statistically significant only for the patients in active disease. Thus, patients in clinical remission display a better preservation of NK function. It is suggested that the study of NK function might offer a helpful tool in following the clinical course and the efficacy of therapy in NHL.

Natural killer cell activity and T subpopulations in thalassemia major.

Natural killer (NK) cell activity against K562 cell targets and the distribution of T cell subpopulations were investigated in the peripheral blood of 25 patients affected by beta thalassemia major, 18 clinically healthy heterozygotes, and 25 age-matched normal subjects. It was found that thalassemia major patients display augmented levels of NK activity [specific lysis 41.9 +/- (se) 4.5%], while thalassemic carriers behave as normal controls [specific lysis 34.6 +/- (se) 3.5%]. The increase of NK function was neither related to the splenectomy nor to the siderosis, but rather to the age and the amount of blood units that the patients had received. An imbalance of circulating T subsets with the helper/suppressor cell ratio significantly diminished (p less than 0.001) was also detected in homozygotes but not in carriers. The finding that NK function is enhanced in homozygous beta thalassemia might be of clinical interest in assessing the risk of development of malignancies in these patients.

In vitro improvement of chlorambucil-induced cytotoxicity by deflazacort and 6-methylprednisolone in B-cell chronic lymphocytic leukaemia.

We examined whether CLL cell chemosensitivity to in vitro exposure to chlorambucil (CLB) might be improved by the presence of deflazacort (DFZ) in comparison to 6-methylprednisolone (PDN). The PDN lethal dose (LD)50 values were low in 5 samples, intermediate in 4 and high in 7. Low, intermediate and high DFZ-LD50 values were detected in 3, 2 and 11 samples, respectively. The CBL-LD50 mean values were significantly reduced at all PDN and at the 4 highest DFZ concentrations. However, a dose-response effect was seen only in the DFZ group. Both CLB-DFZ and CLB-PDN interactions were analysed in 16 samples at 25 different dose-combinations, resulting in 400 comparisons between expected and observed leukaemic cell survival (LCS) values for each group. In particular, 45.75% and 40% dose combinations were synergistic in CLB-DFZ and CLB-PDN groups, respectively. A relatively higher number of antagonistic interactions were observed among CLB-PDN dose combinations, while analogous number of additive interactions were detected. At concentrations of CLB x1 microgram/ml the phenomenon of synergism, regardless of the steroid concentration, did occur more frequently. On the other hand, a more elevated number of antagonistic interactions were counted at CLB 100 micrograms/ ml. In conclusion, both DFZ and PDN synergize in vitro with CLB, especially at low concentrations of the alkylating agent.

Comparison of younger versus older B-cell chronic lymphocytic leukemia patients for clinical presentation and prognosis. A retrospective study of 53 cases.

Fifty-three patients affected with B-cell chronic lymphocytic leukemia (CLL) younger than 50 years and observed in two hematological institutions have been retrospectively evaluated in order to verify whether this disease has different clinico-hematological features at presentation and different prognosis as compared to older cases. In our experience young cases with B-CLL diagnosis, confirmed by immunophenotype in 90.5% of patients, accounted for 7.1% of the whole CLL population. Sex distribution, mean peripheral lymphocyte count, platelet count, distribution among Rai's and Binet's stages, total tumor mass (TTM) score, histological pattern of bone marrow infiltration and lymphocyte doubling time (LDT) were similar to a series of 201 CLL cases older than 50 years. Only hemoglobin mean level was significantly higher in younger patients (13.1 +/- 2.1 vs 12.2 +/- 2.6 g/dl; p < 0.01). The overall median survival was 7.1 years. Rai and Binet staging classifications and TTM score system retained their prognostic value in this CLL population. In addition, cases fulfilling criteria of "smoldering" CLL, had a very long survival (75% survival probability at 16 years). Life-expectancy of younger patients was significantly longer than that of older ones (median survival, 7.1 versus 4.1 years; p < 0.05). However, when the background mortality due to non-CLL related deaths (i.e., cardiovascular complications, epithelial cancers) was removed, survival advantage of young cases disappeared. In conclusion this study confirms that prognosis of young CLL patients can be easily assessed using the current well-defined criteria. Since age is not by itself a criterion for intensifying treatment, further efforts to identify those young CLL patients who qualify for more aggressive therapy should be made.

In vitro chemosensitivity of chronic lymphocytic leukemia B-cells to multidrug regimen (CEOP) compounds using the MTT colorimetric assay.

BACKGROUND: Anthracycline-containing regimens have given controversial clinical results in CLL. Therefore, we explored the in vitro behavior of CLL B-cells after exposure to the compounds included in the most frequently used combination therapy regimen (CEOP). METHODS: A 4-day MTT colorimetric assay was used in vitro to test the effect of CEOP regimen drugs, either alone or in combination, on CLL B-cells. All drugs but mafosfamide, tested in place of cyclophosphamide, were used at concentrations corresponding to the in vivo dosage employed in the CEOP regimen. Chlorambucil was also studied since it represents the standard treatment for this disease. RESULTS: Epirubicin, prednisone and vincristine displayed a cytotoxic effect in 15, 13 and 4 out of 30 samples, respectively. Combinations of the same drugs showed a synergistic effect in 6 out of 13 assays. A cytotoxic effect of chlorambucil was detected in 2 out of 5 responders to the combination of CEOP regimen drugs, and in 3 out of 7 non responders. Mafosfamide induced a reduction in cell survival in 60-80% of the samples, depending on its concentration. CONCLUSIONS: The MTT assay is suitable for evaluating the in vitro chemosensitivity of CLL B-cells to multidrug regimen compounds. In the present study 40% of samples were resistant to CEOP regimen components in vitro. The possible role of MTT in predicting the clinical response to the CEOP regimen should still be established by prospective in vitro and in vivo studies.

Alpha thalassaemia hydrops fetalis in the UK: the importance of screening pregnant women of Chinese, other South East Asian and Mediterranean extraction for alpha thalassaemia trait.

OBJECTIVE: Alpha zero (alpha 0 or alpha-1) thalassaemia is an important genetic risk for women originating from Hong Kong, Singapore, Vietnam, Thailand, the Philippines or South China. Cypriots are also at risk. Carriers of alpha zero thalassaemia trait can be detected by routine haemoglobinopathy screening. When a couple are both carriers, in each pregnancy there is a 25% risk that the fetus will have alpha thalassaemia hydrops fetalis; this is fatal for the fetus and carries serious obstetric and psychological risks for the mother. Most informed couples at risk request prenatal diagnosis and selective abortion. This study investigates the effectiveness of screening, counselling and prenatal diagnosis for alpha thalassaemia hydrops fetalis in the UK. DESIGN: Retrospective analysis of the notes. SUBJECTS: 18 couples attending University College Hospital London for prenatal diagnosis of alpha thalassaemia hydrops fetalis since 1982. RESULTS: The study shows underdiagnosis of both alpha zero thalassaemia trait and alpha thalassaemia hydrops fetalis leading to avoidable stillbirths and complications in pregnancy. CONCLUSION: We recommend early screening for alpha zero thalassaemia trait for all women of Southeast Asian or eastern Mediterranean origin and the offer of prenatal diagnosis when indicated. The diagnosis of alpha thalassaemia hydrops fetalis should be considered in women of the relevant ethnic origin who have a stillbirth, neonatal death, abnormal ultrasound findings at fetal anomaly scanning (especially a large placenta), or who develop pre-eclampsia.

Clinical significance of sIL2R, sCD23, sICAM-1, IL6 and sCD 14 serum levels in B-cell chronic lymphocytic leukemia.

BACKGROUND: The aim of the study was to establish the role exerted by some soluble factors in B-CLL disease mechanisms. MATERIALS AND METHODS: Serum levels of sIL2R, sCD23, sICAM-1, IL6 and sCD14 were detected in 47 B-CLL patients. Thirty-seven out of the 47 cases were in advanced/progressive stage, while the remaining 10 patients were defined as smouldering B-CLL. Twenty normal controls provided the reference values. Serum samples of 24 out 37 advanced/progressive cases were measured before and six months after the start of chemotherapy. RESULTS: The advanced/progressive patients showed significantly higher levels of sIL2R, sICAM-1 and sCD23 as compared to normal subjects. Furthermore, sIL2R, sICAM-1 and IL6 values were significantly higher in advanced/progressive B-CLL than in smouldering B-CLL patients. A statistically significant difference was found between smouldering B-CLL and controls for sCD14 only. sIL2R and sICAM-1 levels directly correlated with total tumor mass (TTM) score, sCD23 with both TTM score and lymphocytosis, and sCD14 with IgG serum values. sIL2R and sCD23 levels lowered significantly after chemotherapy, but only sCD23 and TTM variations after chemotherapy were closely correlated. CONCLUSIONS: sCD23 may be considered the only indicator of tumor mass, while the other soluble factors can be released through different mechanisms. In particular, sICAM-1 seems to correlate with the ability of the tumor to spread, while the sCD14 increase could indicate a role for this soluble factor in preventing infections in B-CLL patients.