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Summary Low-dose alemtuzumab has shown a favourable toxicity profile coupled with good results in terms of efficacy in relapsed/refractory chronic lymphocytic leukaemia (CLL). We conducted a multicentre retrospective study on the routine clinical use of low-dose alemtuzumab in this patient setting. One hundred and eight relapsed/refractory CLL patients from 11 Italian centres were included in the analysis. All patients had an Eastern Cooperative Oncology Group performance status ≤2 and the majority (84%) had adenopathies <5cm. Low-dose alemtuzumab was defined as a total weekly dose ≤45 mg and a cumulative dose ≤600 mg given for up to 18 weeks. The overall response rate was 56% (22% complete remissions). After a median follow-up of 42·2 months, the median overall survival and progression-free survival were 39·0 and 19·4 months, respectively. In univariate analysis, response was inversely associated with lymph node ( P = 0·01) and spleen ( P = 0·02) size, fludarabine-refractoriness ( P = 0·01) and del(11q) ( P = 0·009). Advanced age and del(17p) were not associated with a worse outcome. Cumulative dose of alemtuzumab was not associated to response. Toxicities were usually mild and manageable; severe infections occurred in seven patients (7%) during therapy. This retrospective analysis confirms that low-dose alemtuzumab is a valid and currently used therapeutic option for the treatment of relapsed/refractory CLL. [ABSTRACT FROM AUTHOR]

The article focuses on the stimulation via surface immunoglobulin that is a promoting factor for clonal expansion in chronic lymphocytic leukaemia (CLL). It reports that these molecules often have polyspecific activity and bind to a battery of antigens. It discusses the studies on the same cohort revealed a correlation between an apoptotic response of the CLL cells in vitro to sIgM crosslinking and an unfavourable clinical course.

Renal impairment (RI) is a severe complication throughout the course of multiple myeloma (MM). Bortezomib has been shown to be highly active in MM patients with RI. We designed this retrospective analysis to investigate the safety and efficacy of bortezomib-based therapy in 117 MM patients with RI, 14 cases required dialysis. A total of 603 cycles of bortezomib were administered (median number, five cycles/patient). Ten patients required early discontinuation of bortezomib because of WHO grade IV toxicity. The rate of bortezomib discontinuation in cases with severe, moderate and mild RI was 11%, 5% and 0%, respectively ( P = NS). Overall, 91 episodes of WHO grade III/IV toxicity were observed. At least a partial response was documented in 83/113 evaluable patients (73%), including complete response (19%) and near complete response (8%). The overall response rate was similar across RI subgroups. Reversal of RI was documented in 41% of patients after a median of 2.3 months (range 0.4–7.9). In three of 14 patients on dialysis, renal replacement therapy was discontinued after 1, 1 and 4 months. The 2-yr estimate of response duration and overall survival was 70% and 51%, respectively. In conclusion, bortezomib-based regimens are safe and effective and should be considered as appropriate treatment options for MM patients with any degree of RI. [ABSTRACT FROM AUTHOR]

IGHV mutational status and ZAP-70 or CD38 expression correlate with clinical course in B-cell chronic lymphocytic leukaemia (CLL). The three markers may be discordant in the single case and there is no consensus on their combined use in clinical practise. This multicenter study investigated this issue. Two-hundred and sixty-two Binet stage A patients were studied for the three markers. Sixty patients were profiled with HG-U133A gene expression chips. Disease progression was determined by time from diagnosis to treatment (TTT). The probability of being treatment-free at 3 years was significantly shorter in patients with unmutated IGHV genes ( IGHVunmut 66% vs. 93%, chi square of log-rank = 30, P < 0·0001), ZAP-70 positive (ZAP-70pos 73% vs. 96%, chi square of log-rank = 8·2, P = 0·004) or CD38-positive cells (CD38pos 68% vs. 91%, chi square of log-rank = 21, P < 0·0001). Cox multivariate regression analysis showed that the three markers had an independent predictive value for TTT of similar power. A prognostic system based on presence of none (low-risk), one (intermediate-risk) or two or three (high-risk) markers was generated. Based on such criteria, 56%, 23% and 21% of cases were clustered in low (HR = 1), intermediate [HR = 2·8, 95% confidence interval (CI) 2·4–5·8] and high-risk group (HR = 8·0, 95% CI 3·9–16·2). Specific transcriptional patterns were significantly associated with risk groups. [ABSTRACT FROM AUTHOR]

Although a double autologous peripheral blood stem cell transplant (APBSCT) is an effective therapy for patients (pts) with multiple myeloma and extends progression-free survival and overall survival, pts show a continued pattern of recurrent disease. The feasibility and tolerability of thalidomide (Thal) administered in the post-transplantation period as maintenance therapy was tested in 17 pts at a dose of 100 mg/d starting between 3 and 5 months after the second transplantation and continuing either until toxicity precluded further therapy or until pts had disease progression. After a median administration of 13 months (range: 3–26), 76.5% (13 pts) failed to tolerate Thal because of: transiet ischemic attack (three pts), severe fatigue (two), neutropenia (one), piastrinopenia (one), severe opportunistic infectious (two), erectile impotence (one), gastointestinal toxicity (anorexia with weight loss one), peripheral neuropathy (two). After a median follow-up of 36 months (range: 10–59) from the second transplant, 13 patients attained a CR + near CR (with a conversion rate from 47.1% to 76.5%). In conclusion, Thal as maintenance therapy after double ASCT is associated with low feasibility and high toxicity and could prevent a lengthy use of this antineoplastic agent. [ABSTRACT FROM AUTHOR]

Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented VHDJH clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one VLJL rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s). [ABSTRACT FROM AUTHOR]

Objectives: Solid second primary cancers (SPC) have become an issue of extensive research. The purpose of the present study was to estimate the standardised incidence ratio (SIR) and the absolute excess risk (AER) of SPC in patients with splenic marginal zone lymphoma (SMZL). Methods: We investigated the incidence of additional cancers in 129 patients consecutively diagnosed with SMZL in three Italian haematological centres, asking the cooperating doctors for additional information on initial and subsequent therapies and on the onset and type of second cancers. Results: Twelve SPC were recorded (9.3%); the 3- and 5-yr cumulative incidence rates were 5.5% and 18.3% respectively, with an SIR of 2.03 [95% confidence interval (CI): 1.05–3.56; P < 0.05; AER = 145.81]. Of 12 SPC observed, four were urinary tract neoplasms (SIR, 3.70; 95% CI: 1.01–9.48; P < 0.05; AER = 70.06), four were lung cancers (SIR, 9.16; 95% CI: 1.41–13.25; P < 0.05; AER = 85.50) and the other four were hepatic carcinoma, endometrial cancer, breast cancer and colorectal cancer. Conclusions: Our findings evidence a high frequency of additional cancers in patients with SMZL and suggest that the incidence rate of SPC is significantly different from that expected in the general population. The frequency of cases with urinary tract and lung malignancies in our series is higher than expected. Although confirmatory data are needed, it is our opinion that SMZL patients are at risk of second cancer and should be carefully investigated on diagnosis and monitored during the follow-up. [ABSTRACT FROM AUTHOR]

The aberrant expression of the myelomonocytic antigen CD14 was investigated in 128 untreated patients diagnosed with B-cell chronic lymphocytic leukaemia (B-CLL). A cut-off value of 5 × 109/l CD14-positive cells was chosen for statistical analysis because it showed the best discriminating power among patients with different clinical features. 56 cases had a CD14+ cell count >5 × 109/l. A significant correlation was found between Rai and Binet stages and total tumour mass (TTM) score on one hand, and the absolute CD14+ cell cut-off, on the other. This relationship was more evident in Rai 0–II and Binet A–B stages, where a CD14+ cell count >5 × 109/l was preferentially distributed among patients with a higher tumoral mass. In univariate analysis the survival probability at 5 and 10 years showed a significant correlation with Rai and Binet stages, TTM score, CD14+ absolute cell count and median age. The median overall survival (OS) was 63 months for patients with a CD14+ cell count >5 × 109/l and 136 months for those with a CD14+ cell count < 5 × 109/l. In the multivariate Cox regression model, Rai stage, age and CD14+ cell count were independent significant factors for the prediction of OS. Finally, when the same analysis was restricted to Rai stages 0–II, CD14+ cell count was the only significant independent parameter influencing OS, with a relative death risk of 3.8. In conclusion, these data reveal that CD14+ represents an important marker for predicting OS in B-CLL patients and, therefore, we suggest that it should be included in the immunological characterization of B-CLL. [ABSTRACT FROM AUTHOR]

We investigated the possible value of an in vitro drug-induced cytotoxicity assay in predicting clinical response to fludarabine (FAMP) in chronic lymphocytic leukaemia (CLL). The median FAMP-LD50 values for cases designated as complete response (CR), partial response (PR), no response (NR) and progressive disease (PD) were 1.43, 2.05, 24.8 and 77.9 μg/ml, respectively (P=0.013). A significant lower mean FAMP-LD50 value was observed in the in vivo responding cases as compared to non-responding ones (3.0 ± 0.82 SEM v 42.3 ± 12.6 SEM, P=0.001). Only FAMP-LD50 ≤ 2.5 μg/ml and more than four FAMP courses significantly influenced the response rate in univariate and multivariate analyses. The MTT assay may be of value in predicting clinical response to FAMP in CLL patients. [ABSTRACT FROM AUTHOR]

The recent development of reduced intensity conditioning and allotransplantation (RICT) has opened a new way to assure engraftment of donor cells while reducing early transplant-related mortality. We evaluated the combination of high-dose therapy and autologous peripheral blood stem cells transplantation (APBSCT) followed by RICT to extend the benefit of allografting procedures in de novo multiple myeloma (MM) patients. Fifteen subjects with stage III MM (median age 51 years, range 40-57) received high dose melphalan (200 mg/m(2)) followed by APBSCT previously collected after cyclophosphamide (4 g/m(2)) and granulocyte colony-stimulating factor (G-CSF). After 3-4 months from APBSCT, the patients underwent RICT, consisting of fludarabine 30 mg/m(2) + cyclophosphamide 300 mg/m(2) on days -4, -3, and -2. Acute graft-versus-host disease (GVHD) occurred in 2 patients; 6 patients developed chronic GVHD; 4 patients developed CMV antigenemia and were treated pre-emptively with ganciclovir. No transplant related mortality was shown. Response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF); when IF was negative, patients were classified in complete remission (CR) and when it remained positive, near CR (nCR). After a median follow up of 44 months post APBSCT, 100 and 43% of patients are still alive and progression-free, respectively. Overall, the CR + nCR rate after dose-reduced allograft was enhanced from 26.7 to 73.3%. A correlation not statistically significant between GVHD and remission was found. In conclusion, an up-front tandem strategy with a very low reduced intensity-conditioning regimen for allografting following autografting is feasible and induces high CR/nCR rate in MM.