Raffaella Marcheselli

Bisphosphonate-associated osteonecrosis of the jaw: A review of 35 cases and an evaluation of its frequency in multiple myeloma patients

Over a period of 28 months, we observed five cases of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates (BP) at our institution. This prompted us to undertake a retrospective, multicenter study to analyse the characteristics of patients who exhibited ONJ and to define the frequency of ONJ in multiple myeloma (MM). We identified 35 cases in Gruppo Italiano Studio Linfomi centers during the period 2002 – 05. The median time from cancer diagnosis to the clinical onset of ONJ was 70 months. In these 35 cases of ONJ, 24 appeared 20 – 60 months after starting BP treatment. The time for the onset of ONJ was significantly shorter for patients treated with zoledronic acid alone than for those treated with pamidronate followed by zoledronic acid. The frequency of ONJ in the MM group during the study period was 1.9%, although the nature of the present study may have resulted in an underestimation of ONJ cases. Our analysis strongly suggested an association between the use of BP and the occurrence of ONJ, although we were unable to identify any definite risk factors with a retrospective study. The most frequently ONJ-associated clinical characteristics were chemotherapy treatment, steroid treatment, advanced age, female sex, anemia, parodonthopaties/dental procedures and thalidomide (in the case of MM patients).

Secondary malignancies after treatment for indolent non-Hodgkin’s lymphoma: a 16-year follow-up study

There is relatively little information on secondary cancers after non-Hodgkin’s lymphomas. This long-term follow-up study determines the incidence rate and identifies subgroups of non-Hodgkins lymphoma patients with increased incidences of secondary malignancy. Background Relatively little information is available on the incidence of secondary cancer in non-Hodgkin’s lymphoma. The aim of this long-term follow-up study was to determine the incidence, the time free of second tumors, and risk factors for developing secondary cancer in a homogeneous group of patients with non-Hodgkin’s lymphoma. Design and Methods We evaluated a total of 563 patients with indolent non-Hodgkin’s lymphoma enrolled in Gruppo Italiano Studio Linfomi trials from 1988 to 2003. Results After a median follow-up of 62 months, 39 patients (6.9%) developed secondary cancer: 12 myelodysplastic syndromes/acute myeloid leukemia, and 27 solid tumors. The overall standardized incidence ratio of secondary malignancy in patients with non-Hodgkin’s lymphoma was higher than the risk of malignancy in the general population. The standardized incidence ratio was elevated in male patients and in patients under 65 years old at first treatment. Overall, the cumulative incidence of secondary cancer at 12 years was 10.5%, after correction in a competing-risk model. Univariate and multivariate Cox regression analyses showed that older age at the time of diagnosis, male sex, and fludarabine-containing therapy had significant negative impacts on the time free of second tumors. Conclusions We have identified subgroups of non-Hodgkin’s lymphoma patients with increased standardized incidence ratios of secondary malignancy and variables that have a negative impact on the time free of second tumors. This information could help physicians to select the most appropriate treatments. Finally, taking into account the possible occurrence of secondary neoplasia, long-term monitoring must be considered.

Prognostic models for diffuse large B-cell lymphoma in the rituximab era: a never-ending story

BACKGROUND Improved treatment have modified survival outcome in patients with diffuse large B-cell lymphoma (DLBCL) and altered the importance of previously recognized prognostic markers. DESIGN AND METHODS To evaluate International Prognostic Index (IPI) score before and after rituximab introduction and to validate the absolute lymphocyte count (ALC)/revised International Prognostic Index (R-IPI) model, we carried out a retrospective analysis on a total of 831 patients with DLBCL. RESULTS Our results show that IPI lost its discriminating power with the introduction of rituximab. The analysis of our second set allowed us to validate the ALC/R-IPI model. The R-IPI and ALC/R-IPI could still be used for designing clinical trials, but both have difficulty recognizing a high percentage of poor prognosis patients, though it remains an important goal of a good prognostic model considering the modest impact of salvage treatments on survival. CONCLUSIONS A new model on the basis of significant variables in the rituximab era and built on a large database of patients treated with rituximab is urgently needed. As prognostic models are changing with the efficacy and mechanisms of action of treatment utilized, looking for a new prognostic score is a never-ending story in which researchers are trying to hit a continuously moving target.

Survival of multiple myeloma patients in the era of novel therapies confirms the improvement in patients younger than 75 years: a population-based analysis.

Novel treatments for multiple myeloma (MM) have shown promising results in clinical trials, but the advantage in unselected patients is still unclear. In order to evaluate whether novel therapies impact survival of MM patients, we performed a population‐based analysis on data collected by the Modena Cancer Registry from 1989 to 2009. The analysis evaluated 1206 newly diagnosed MM patients collected in the years 1988–96 (conventional therapy), 1997–05 (high dose melphalan and autologous transplant), and 2006–09 (novel agents era). Both relative survival (RS) and overall survival (OS) improved over the years, but not equally in the three groups. For patients aged <65 years, RS improved in 1997–05 and 2006–09 compared with previous years and a trend to improvement was observed from 1997–05 to 2006–09. For patients aged 65–74 years, RS improved significantly in 2006–09 compared with 1988–96 and 1997–05. No amelioration was observed for patients 75+ years old. OS confirmed RS. In conclusion, the survival of MM patients aged <65 and, in particular, 65–74 years, has improved over time, especially after 2006. This observation provides circumstantial evidence that novel therapies might impact patient survival. Despite the limits of this study, these data refer to an unselected population, giving a picture of every day clinical practice.

Radiation therapy improves treatment outcome in patients with diffuse large B-cell lymphoma

The effects of radiotherapy (RT) after chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) remain unclear; several trials have yielded conflicting results. This study examined the effect of RT after cyclophosphamide, doxorubicin, vincristine, and prednisone + rituximab (R-CHOP) treatment on event-free (EFS) and overall (OS) survival. Data from 216 patients with DLBCL who were enrolled in two clinical trials at Italian Lymphoma Study Group sites and were subjected to six R-CHOP cycles and involved-field radiotherapy (IFRT) were retrospectively analyzed. IFRT treatment yielded significant EFS benefit, with a 66% reduction in the risk of death and/or disease progression. Cox analysis, when adjusted for age, gender, stage, performance status (PS), lactate dehydrogenase (LDH), and disease bulk, confirmed the significant EFS benefit of IFRT. The role of RT in DLBCL in the rituximab era is unclear. Future studies must take into account new radiation techniques and the response to chemotherapy based on functional imaging. Prospective randomized trials incorporating response-adapted therapy and modern radiation techniques are needed.

Risk for second malignancies in non-Hodgkin’s lymphoma survivors: a meta-analysis

BACKGROUND Late side-effects are becoming an important issue in non-Hodgkins lymphoma (NHL) survivors. We intended to estimate pooled relative risk (RR) of secondary malignant neoplasms (SMNs), to evaluate site-associated RR and the impact of different treatments. DESIGN We carried out an electronic search of Medline and EMBASE seeking articles investigating the risk of SMNs and reporting RR measures. The studies were evaluated for heterogeneity before meta-analysis and for publication bias. Pooled RRs were estimated using fixed- and random-effects models. RESULTS A total of 23 studies met the inclusion criteria. Pooled RRs of SMNs overall and for solid tumors were 1.88 and 1.32, respectively. We found an excess of risk for several specific cancer sites. Radiotherapy alone did not increase the risk for SMNs, while chemotherapy and combined treatments augmented the RR. Regression analyses revealed a positive significant association for all SMNs with total body irradiation, and for solid SMNs with younger age. No publication bias was observed. CONCLUSIONS Our results indicate that NHL patients experience a higher risk for SMNs than the general population and that various treatments have different impact on RR. More information will be necessary to evaluate possible interactions with genetic susceptibility and environmental exposure.

Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma

The current study was conducted to asses the safety profile and clinical activity of rituximab in combination with fludarabine and cyclophosphamide in patients with recurrent follicular lymphoma (FL).

Second malignancies after treatment of diffuse large B-cell non-Hodgkin's lymphoma: a GISL cohort study

Improved treatment has increased the life expectancy of patients with non-Hodgkin’s lymphoma, but the risk of second cancer in patients treated for diffuse large B-cell lymphoma is unclear. This Italian study shows that only young patients have an increased incidence ratio of second malignancies, while the incidence ratio in patients aged over 59 years matched that in the Italian general population. Background Improved treatment has increased the life expectancy of patients with non-Hodgkin’s lymphoma, but few studies have addressed the issue of second cancer in patients treated for diffuse large B-cell lymphoma. The aims of this study were to determine the incidence and time free of second cancers in this subset of patients. Design and Methods We evaluated a cohort of 1280 patients with diffuse large B-cell lymphoma who were first treated between 1988 and 2003. We utilized the central database of the Gruppo Italiano Studio Linfomi, which includes data on demographics, clinical characteristics, laboratory parameters, treatment and follow-up of all patients with non-Hodgkin’s lymphoma enrolled in clinical trials. Results After a median follow-up of 51 months, 48 patients had developed a second cancer: 13 hematologic malignancies and 35 solid tumors. The overall standardized incidence ratio in our cohort (with a median age of 58 years) matched that of the general Italian population. The incidence ratio of second tumors was age related, and the age groups 20–39 and 40–59 years showed an increased risk. Overall, the cumulative incidence of second cancer was 8.2% at 15 years. A multivariate analysis showed that older age at the time of diagnosis of lymphoma had a negative influence on the time free of second tumors. Conclusions In our cohort, only young patients showed an increased incidence ratio of second malignancies, while the incidence ratio in patients aged over 59 years matched the incidence in the Italian general population. Demographics, baseline characteristics, laboratory parameters and treatment modalities did not have any significant impact on the incidence ratio of a second cancer.

A randomized trial with melphalan and prednisone versus melphalan and prednisone plus thalidomide in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplant

Several trials comparing the efficacy of standard melphalan and prednisone (MP) therapy with MP plus thalidomide (MPT) in elderly patients with multiple myeloma (MM) have been reported, with inconsistent results. The primary goal of our study was to evaluate the efficacy and toxicity of MP versus MPT in newly diagnosed patients with MM who were transplant-ineligible or over age 65. A total of 135 patients were enrolled. Either minimal response or better or partial response or better were more frequent with MPT treatment (p = 0.001). After a median follow-up of 30 months, median progression-free survival (PFS) and overall survival (OS) were 33 and 52 months for MPT versus 22 and 32 months for MP, respectively. The comparison showed a significant advantage for MPT versus MP in PFS (p = 0.02) and only a trend for OS (p = 0.07). Severe adverse events were observed more frequently with MPT. In conclusion, our results show an improved activity of MPT at a cost of increased toxicity. We believe that MPT can be considered one of the new standard of care for elderly or transplant-ineligible patients with MM.

Bisphosphonates-associated osteonecrosis of the jaw: A long-term follow-up of a series of 35 cases observed by GISL and evaluation of its frequency over time

Aims of the study were long term follow-up (FU) of bisphosphonates-associated osteonecrosis of the jaw (ONJ) in 35 cases observed by Gruppo Italiano Studio Linfomi (GISL) between 2002 and 2005 and the evaluation of its frequency in multiple myeloma patients over time. We asked the centres to up-date cases with ONJ, and to report new cases of ONJ diagnosed between 2006 and 2008. After a median FU of 31 months, 19 patients are alive, 13 died, mainly from progression of the primary disease, and three patients are lost to follow-up. Treatment was mainly conservative, however, nine patients underwent surgery. Overall improvement was reported in 13 patients, 11 stabilized, and eight patients progressed. One patient relapsed after dental procedure. ONJ impacted quality of life, causing pain and interfering with the ability to eat. Although the frequency of ONJ in myeloma patients in the period 2006-2008 was slightly increased (3.6% vs. 1.9% in 2002-2005), we confirm the rarity of the complication.