Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib.

For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine kinase inhibitors (TKIs) raised a debate on treatment optimization. The debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies, some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic-phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (⩽10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but as 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also because of second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.

Differences among young adults, adults and elderly chronic myeloid leukemia patients.

BACKGROUND: The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage. PATIENTS AND METHODS: To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period. RESULTS: Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011). CONCLUSIONS: The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome. CLINICAL TRIAL NUMBERS: NCT00510926, NCT00514488, NCT00769327, NCT00481052.

Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib.

Several retrospective studies have described the clinical manifestation of peripheral artery occlusive disease (PAOD) in patients receiving nilotinib. We thus prospectively screened for PAOD in patients with chronic phase chronic myeloid leukemia (CP CML) being treated with tyrosine kinase inhibitors (TKI), including imatinib and nilotinib. One hundred and fifty-nine consecutive patients were evaluated for clinical and biochemical risk factors for cardiovascular disease. Non-invasive assessment for PAOD included determination of the ankle-brachial index (ABI) and duplex ultrasonography. A second cohort consisted of patients with clinically manifest PAOD recruited from additional collaborating centers. Pathological ABI were significantly more frequent in patients on first-line nilotinib (7 of 27; 26%) and in patients on second-line nilotinib (10 of 28; 35.7%) as compared with patients on first-line imatinib (3 of 48; 6.3%). Clinically manifest PAOD was identified in five patients, all with current or previous nilotinib exposure only. Relative risk for PAOD determined by a pathological ABI in first-line nilotinib-treated patients as compared with first-line imatinib-treated patients was 10.3. PAOD is more frequently observed in patients receiving nilotinib as compared with imatinib. Owing to the severe nature of clinically manifest PAOD, longitudinal non-invasive monitoring and careful assessment of risk factors is warranted.

Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib.

Health-related quality of life (HRQOL) is an important goal of therapy for chronic myeloid leukemia (CML) patients treated with current molecular-targeted therapies. The main objective of this study was to investigate factors associated with long-term HRQOL outcomes of CML patients receiving imatinib. Analysis was performed on 422 CML patients recruited in an observational multicenter study. HRQOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Key socio-demographic and clinical data were investigated for their association with HRQOL outcomes. Chronic fatigue and social support were also investigated. Univariate and multivariate linear regression analyses were used to identify independent factors associated with HRQOL outcomes. Fatigue was the only variable showing an independent and consistent association across all physical and mental HRQOL outcomes (P<0.01). Differences between patients reporting low versus high fatigue levels were more than eight and seven times the magnitude of a clinically meaningful difference, respectively, for the role physical (Δ=70 points) and emotional scale (Δ=63 points) of the SF-36. Fatigue did not occur as an isolated symptom and was most highly correlated with musculoskeletal pain (r=0.511; P≤0.001) and muscular cramps (r=0.448; P≤0.001). Chronic fatigue is the major factor limiting HRQOL of CML patients receiving imatinib.

Clinico-biological implications of increased serum levels of interleukin-8 in B-cell chronic lymphocytic leukemia.

BACKGROUND AND OBJECTIVE: Constitutive cellular expression and serum release of biologically active interleukin-8 (IL-8) has been reported in B-cell chronic lymphocytic leukemia (CLL). Given the autocrine role played by IL-8 in the process of cell accumulation characteristic of this disease we tried to investigate clinico-biological implications of increased serum levels of this cytokine in an unselected series of B-cell CLL patients. DESIGN AND METHODS: Serum levels of IL-8 were determined at the time of diagnosis in 58 previously untreated B-CLL patients using an immunoenzyme assay. Results were correlated with main clinico-hematologic features as well as with the risk of disease progression. Finally, we looked for associations between IL-8 and molecules directly involved in apoptosis, such as intracellular bcl-2 and soluble APO-1/Fas. RESULTS: Increased serum levels of IL-8 were found in 15 out of 58 (25.8%) B-cell CLL patients. Serum levels of IL-8 did not reflect clinico-biological features representative of tumor mass such as clinical stage, histopathologic pattern of bone marrow (BM) involvement, b2-microglobulin, sCD23 and sCD27 titers. Interestingly, circulating levels of IL-8 paralleled those of intracellular bcl-2 (r = 0.522; p = 0.01), thus confirming that the antiapoptotic effect of IL-8 can be exerted through a bcl-2 dependent pathway. Levels of IL-8 did not match those of soluble Apo-1/Fas (r = -0.013; p = 0.943). Finally, stage A patients with levels of IL-8 above the median value (i.e. 4.5 pg/mL) were more likely to progress to a more advanced clinical stage than those with levels below the median value (p < 0.05). INTERPRETATION AND CONCLUSIONS: IL-8 is an interesting marker in B-cell CLL, closely involved in the pathogenesis of disease. Furthermore, it is useful for predicting the pace of disease progression in early clinical stages.

Clinico-prognostic implications of simultaneous increased serum levels of soluble CD23 and beta2-microglobulin in B-cell chronic lymphocytic leukemia.

Soluble CD23 (sCD23) and beta-2 microglobulin (beta2-m) are reliable prognostic parameters in B-cell chronic lymphocytic leukemia (CLL); however, their merit over well-established clinical variables such as clinical stages, bone marrow (BM) histology and lymphocyte doubling time (LDT) remains to be defined. Furthermore, information dealing with the impact on overall survival of the simultaneous increase of either beta2-m or sCD23 are lacking. In this prospective study based on 106 B-cell CLL patients, we propose a combination of beta2-m and sCD23 as a strong prognostic system whose statistical significance was mainly due to an excess of deaths in the subgroup displaying increased serum levels of either beta2-m or sCD23. Multivariate survival analysis confirmed the important dominant role of such a finding, thus excluding features with a high degree of codependence (i.e. clinical stages, LDT) and including variables with low association (i.e. BM histology) in the final regression model. The presence of increased serum levels of beta2-m/sCD23 and diffuse BM histology signified high-risk disease, whereas the absence of any adverse variable was associated with prolonged survival; in between there was a subgroup with only 1 characteristic which displayed an intermediate pattern of survival. Finally, on the basis combined increased serum levels of beta2-m and sCD23, a better stratification of low- and intermediate-risk patients could be obtained, thus allowing the formulation of a clinico-biological staging for CLL.

Increased bcl-2/bax ratio in B-cell chronic lymphocytic leukemia is associated with a progressive pattern of disease.

In order to evaluate clinical implications of altered expression of bcl-2 and bax proteins in B-cell chronic lymphocytic leukemia (CLL) we studied 27 patients with this disease. Cytofluorometric levels of bcl-2 did not reflect the status of disease. In contrast bax expression was lower in progressive than in non-progressive disease, therefore leading to a higher bcl-2/bax ratio in patients of the former group. If confirmed in longitudinal studies, quantitative cytofluorometric evaluation of bcl-2 and bax protein might help to identify patients with progressive disease who could possibly benefit from early therapy.

Nutritional survey of children and adolescents with myelomeningocele (MMC): overweight associated with reduced energy intake.

UNLABELLED: In patients affected by MMC both neurological and systemic dysfunctions may cause obesity and malnutrition. The aim of this study is a nutritional survey, with anthropometric assessment and dietary evaluation, of patients affected by MMC. CLINICAL MATERIALS AND METHODS: Anthropometric assessment, dietary evaluation, and a comprehensive assessment of motor impairment degree (MID) were performed in 100 patients (54 males, 46 females) affected by MMC aged from 6 to 228 months (median 91 months). RESULTS: Fifty-five/100 children and adolescents with MMC were classified as normal or wellnourished and 5 at risk of malnutrition or malnourished, while another 40/100 patients were classified as marked overweight (weight-for-height or BMI above the 95th percentile). Deficit in height-for-age was observed in 34/100 patients; 12 of these patients presented with obesity. Dietary assessment evidenced that the majority of wellnourished patients (48/55) were consuming less than 80% or between 80% to 100% of recommended daily allowances (RDA) of energy. Overweight patients had an energy intake lower than their own RDA: 5 below 80%, 25 between 80% to 100%, and only 10 over 100% of RDA of energy for age and sex. No statistical correlation was found between nutritional status and MID, while there was a statistically significant difference between nutritional status and dietary intake (p = 0.005). DISCUSSION: Overweight is the most frequent nutritional disease in patients affected by MMC. Since in our experience on correlation with MID was found, we can speculate that childhood and adolescent obesity in patients with MMC occurs as a result of complex interactive factors, not strictly related to energy intake and MID. Nutritional surveillance and specific treatment programs for overweight MMC patients are essential to enhance their quality of life.

Patterns of inheritance in Irish and Italian families with neural tube defects: comparison between high and low rate areas.

Neural tube defects (NTDs) may result from a genetic susceptibility interacting with environmental exposures occurring early in pregnancy. Current research is concerned with enlarging our understanding of the action of folic acid, a B group vitamin, which has been shown to prevent the occurrence of NTDs in clinical trials. Despite the epidemic waves in the incidence of NTDs and the existence of areas with very high rates, there have been few studies that explored the genetic contribution to NTDs in high rates versus low rate areas. We investigated the genetic epidemiologic factors that occur in NTD families and compared their frequency in a high rate area-Ireland-with a low rate area-Italy. We explored the existence of three features indicative of hereditary factors and found that all three factors were higher in Ireland than in Italy. These factors were (i) sibling recurrence risk (3.3% vs 1.6%; p = 0.2), (ii), other malformations in siblings (11.5% vs 3.3%; p < 0.001) and (iii) average number of children in mothers' families vs fathers' families (average difference in Ireland 1.0 vs 0.4 in Italy; p < 0.1). These results support the motion that geographic differences in occurrence of NTDs are due at least in part to differing prevalences of genetic susceptibility factors. Further epidemiological and molecular studies are needed to confirm this observation. In addition, studies of the interactions between environmental agents and genetic susceptibility will be important in determining their relative contributions.

Multigeneration maternal transmission in Italian families with neural tube defects.

Periconceptional vitamin supplementation with folate prevents about three-quarters of expected cases of neural tube defects (NTDs) in clinical trials. However, vitamin action may be regulated at the level of the gene, and individual susceptibility to environmental agents, including dietary components, also may be under genetic control. We investigated the presence of familial factors in a retrospective case control study of neural tube defects in Genoa, Italy. Cases included all patients treated at a single pediatric neurosurgical service. Controls matched on age and sex came from the same hospital. We found strong evidence for the contribution of genetic factors in this study. There was an excess risk of 14 for the occurrence of NTDs in first-degree relatives compared to controls (P < .0005). There was no difference in sex ratio in any group of relatives, but maternal grandparents of children with a high spinal lesion had 14% fewer off-spring than paternal grandparents (P < .005), possibly because of excess miscarriages. Our study is the first to show complex patterns of inheritance in spina bifida families affecting three generation in one clinical subgroup and preferentially on the mother's side. These results support a role for genomic imprinting and highlight the value of multidisciplinary epidemiologic and clinical studies that include multiple generations. New studies incorporating dietary and genetic approaches will help clarify and extend these findings.

Expression on leukemic cells and serum circulating levels of intercellular adhesion molecule-1 (ICAM-1) in B-cell chronic lymphocytic leukemia: implications for prognosis.

Expression of intercellular adhesion molecule-1 (ICAM-1) has been correlated clinical and laboratory characteristics of 62 patients with untreated CD5+ chronic lymphocytic leukemia (CLL). ICAM-1 was detected on B-CLL cells from 19 out of 62 patients (30.6%) and its expression did not correlate with the majority of immunological markers. An important finding of this study was the association between ICAM-1 expression and mean fluorescence intensity (MFI) of Slg (r = 0.507; P < 0.001). As far as correlation with clinical parameters is concerned, a statistically significant association between Binet clinical stages and ICAM-1 expression was found (P < 0.05). Furthermore, an atypical CLL morphology was more frequently encountered among patients who expressed ICAM-1 (P < 0.005). To obtain more information on the role of ICAM-1 in CLL we measured serum levels with a sandwich enzyme immunoassay. In 47 B-cell CLL patients studied, the mean value of circulating ICAM-1 levels was significantly higher (561 +/- 201 ng/ml) than that observed in 25 normal controls (353 +/- 162 ng/ml; P < 0.005); a clear correlation being found with Binet clinical stages (P = 0.026) and bone marrow (BM) histology (P < 0.005). We conclude that circulating ICAM-1 is elevated in CLL and such an increase reflects tumor mass as defined by clinical stages and BM histology, rather than peripheral blood lymphocytosis (r = 0.240). Even if soluble ICAM-1 appears to be less specifically increased that soluble CD23 serum levels, these circulating molecules were not completely independent of each other (r = 0.512; P < 0.001).

Cytogenetics of the tissue involved in neural tube defects.

Cytogenetic techniques were used to study the tissue involved in neural tube defects. Eighteen patients have been evaluated and no specific alterations have been detected. We conclude that, whatever are the mechanisms that lead to neural tube defect, their origins must be searched for at the molecular level.

Infections in chronic lymphocytic leukemia. Analysis of incidence as a function of length of follow-up.

BACKGROUND AND METHODS: Infections represent the major cause of death in chronic lymphocytic leukemia (CLL); however, clinical studies dealing with their incidence have yielded inconclusive results. In order to address this issue we reviewed the records of 125 CLL patients (mean age 65.6 yrs; 81 M/44 F; Stage A, 48; Stage B, 37; Stage C, 40) followed up at our institution over a 10-year period. RESULTS: The 125 patients accrued 447 person-years, a mean of 3.8 years per person. There were 199 recorded infections: 47 severe (crude rate 9.8 per 100 person-years) and 72 moderate, respectively. The 5-year risk of developing a severe infection for the whole series was 26% (95% CI: 24.7-27.3%), and 21 out of 71 deaths (29.5%) could be attributed to infectious causes. Despite a linear trend toward increased risk (r = 0.98), hazard function analysis showed a constant pattern of risk (r = 0.30), suggesting a lack of correlation of this event with time. Furthermore, the 5-year risk of developing a severe infection increased to 57.1% (95% CI: 36.4-77.8%) for patients with low IgG levels (less than 6.5 gr/L), and to 68% for those with both low IgG levels and disease stage C. On the other hand, patients who experienced a severe infection more frequently had advanced clinical stage (P < 0.001), low IgG levels (P < 0.01) and diffuse bone marrow (BM) histology (P < 0.05). CONCLUSIONS: Infection is a constant risk in CLL that is associated with shortened survival. Factors such as hypogammaglobulinemia and advanced disease appear to be the major predisposing factors.

Combined use of interferon alpha-2, chlorambucil and prednisone in previously treated patients with low-grade non-Hodgkin's lymphomas. Results of a phase II study.

AIMS AND BACKGROUND: To investigate therapeutic activity and safety of alpha-interferon (alpha-IFN) in combination with chlorambucil (CLB) and prednisone (PDN), we treated 9 low-grade non-Hodgkin lymphoma patients with clinical evidence of relapsed (5 cases) or resistant (4 cases) disease with such an association. METHODS: In all instances, treatment consisted of alpha-2a IFN administered by subcutaneous route thrice weekly for 3 weeks, CLB, 5 mg/day for 21 days, and PDN, 30 mg three times a week for 3 weeks. Cycles were repeated every 28 days. RESULTS: A well-documented clinical response was observed in 6 (4 CRs+2 PRs) of 9 patients. Interestingly, 3 of 4 CRs were achieved in patients with histologically proven bone marrow involvement. Median duration of response was 18.5 months (range, 4-29 months). Myelosuppression was a common side effect. Two patients experienced grade 3 hematologic toxicity which did not preclude continuation of therapy. CONCLUSIONS: As new purine analogues are not currently available, the combination of alpha-IFN, CLB, and PDN may represent, in our opinion, a valid therapy for patients not eligible for aggressive therapy such as autologous bone marrow transplantation.