Improving the international prognostic index score using peripheral blood counts: Results of a large multicenter study involving 520 patients with diffuse large B cell lymphoma.

The main purpose of this study was to assess whether it is possible to improve the prognostic impact of international prognostic index (IPI) score by combining it with peripheral blood counts. Thus, we evaluated the prognostic power of lymphocyte, neutrophil, and monocyte counts in 520 patients with diffuse large B cell lymphoma treated with R-CHOP, confirming that these parameters have a strong impact on overall survival (OS). Using revised IPI (R-IPI), 44% of patients were categorized as poor-risk and showed an OS at 5 years of 46%. As OS at 5 years of the 520 patients is 67%, it is clearly evident that R-IPI tends to overestimate the proportion of patients with poor prognosis. Accordingly, in an attempt to improve the discriminating power of R-IPI, we evaluated and compared three different scores by combining the neutrophil lymphocyte ratio (NLR) and absolute monocyte count (AMC) with the following values: (a) IPI score 3-5, (b) age > 60 years and performance status, (c) age ≥ 65 years and LDH > ULN. The three indexes studied, had a similar 5 years OS for the high-risk group (46%-52%), but the proportion of patients classified as poor-risk were 37%, 20%, and 32%, respectively, which are lower than 44% identified with R-IPI. Thus, while R-IPI overestimates the number of high-risk patients, after applying our models, it is possible to recognize patients who are truly at high-risk. Of the three scores, the most accurate appears to be that based on NLR, AMC, LDH > ULN and age ≥ 65 years, which identifies 32% of high-risk patients, correlating well with what is seen in clinical practice.

The classic prognostic factors in advanced Hodgkin's lymphoma patients are losing their meaning at the time of Pet-guided treatments.

The International Prognostic Score (IPS) is the most commonly used risk stratification tool for patients with advanced Hodgkin lymphoma (HL). It incorporates seven clinical parameters independently associated with a poorer outcome: male sex, age, stage IV, hemoglobin level, white blood cell and lymphocyte counts, and albumin level. Since the development of the IPS, there have been significant advances in therapy and supportive care. Recent studies suggest that the IPS is less discriminating due to improved outcomes with ABVD therapy. The aim of the present study was to asses if classic prognostic factors maintain their prognostic meaning at the time of response-adapted treatment based on interim PET scans. We evaluated the prognostic significance of IPS in the 520 advanced stage HL patients enrolled in the PET-guided, HD0801 trial in which PET2-positive patients underwent a more intense treatment with an early stem-cell transplantation after 2 cycles of ABVD. We observed that in these patients, the IPS completely loses its prognostic value together with all the single parameters that contribute to the IPS. Furthermore, neutrophils, monocytes, lymphocytes, and the ratio among them also no longer had any predictive value. We believe that the substantial improvement in survival outcomes in PET2-positive patients treated with early autologous transplantation could explain the complete disappearance of the residual prognostic significance of the IPS.

Neutrophil-lymphocyte ratio at diagnosis is an independent prognostic factor in patients with nodular sclerosis Hodgkin lymphoma: results of a large multicenter study involving 990 patients.

Several studies have demonstrated the prognostic value of neutrophil-lymphocyte ratio (NLR) in patients with solid tumors and non-Hodgkin lymphoma. In contrast, there is only sparse data on its prognostic role in patients with classical Hodgkin lymphoma (cHL). The aim of our study was to establish whether NLR could serve as an independent prognostic factor in a cohort of 990 patients with nodular sclerosis (NS)-cHL. After analysis of the log hazard ratio (HR) as a function of NLR, we chose the value 6 as cutoff. Patients with NLR >6 had a worse progression-free survival and overall survival compared to those with NLR ≤6; 84% vs 75% and 92% vs 88%, at 5 years, with an HR of 1.65 and 1.82, respectively. Multivariate analysis showed that the risk remained high with HR 1.44 and HR 1.54 in progression-free survival and overall survival, respectively. In summary, our study shows that NLR is a robust and independent prognostic parameter in NS-cHL, both in early and advanced disease. It is inexpensive and simple to apply. Thus, we conclude that NLR, possibly in combination with the international prognostic score and absolute monocyte count, is a useful guide for physicians treating NS-cHL patients.

A Multicenter Phase II Study of Twice-Weekly Bortezomib plus Rituximab in Patients with Relapsed Follicular Lymphoma: Long-Term Follow-Up.

Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control.

Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide.

Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM.

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.

Impact of body composition, nutritional and inflammatory status on outcome of non-small cell lung cancer patients treated with immunotherapy.

BACKGROUND AND AIMS: Body composition and balance of nutritional and inflammatory status are important for the immune system. Alterations of these aspects may impact on response, outcome and toxicities of immunotherapy. In this review we try to clarify some definitions and tools used for the assessment of the different aspects of nutritional disorders, body composition and inflammatory status with a focus on lung cancer. METHODS: We primary investigate the definitions of malnutrition, cachexia, sarcopenia and overweight. Secondary, tools used to measure body composition, nutritional and inflammatory status, mainly in lung cancer are reviewed. RESULTS: All these features, in the time of precision medicine may improve assessment and selection of patients, incorporating also early palliative care in standard therapy. CONCLUSIONS: A multimodal approach based on nutrition assessment and physical exercise should be evaluated to improve aspects of the immune response against cancer and to propose the best treatment to every patient.

Body composition and inflammation impact in non-small-cell lung cancer patients treated by first-line immunotherapy.

Background: Immunotherapy changed the landscape of non-small-cell lung cancer (NSCLC). Efforts were made to implement its action. This study aims to describe body composition, nutritional and inflammatory status in NSCLC patients treated by first-line immunotherapy, their correlation, variation and impact. Patients and methods: We retrospectively analyzed 44 consecutive patients who received pembrolizumab treatment. Results: During the therapy, inflammation and visceral fat increased, whereas muscle and subcutaneous fat decreased. Parameters related to inflammation had an interesting prognostic impact. High numbers of white blood cells remained significantly correlated with a high risk of death in multivariate model. Conclusion: For the best treatment choice, a combination of clinical and biological factors will be most likely be necessary. Prospective and larger studies with a multidimensional approach are needed.

Lay abstract Inflammation and malnutrition in cancer patients may affect the immune system and response to therapy. We noticed an increase in inflammation and visceral fat and a decrease in muscle and subcutaneous fat during therapy. No variation showed a significant correlation with survival. Muscle mass, adipose tissue and body mass index do not confirm any prognostic impact or relationship with response to therapy. More interesting results were observed with parameters related to inflammation. Probably, for the best treatment choice, a combination of clinical and biological factors will be necessary. Further studies with a multidimensional approach are needed to propose the best treatment and the best support to everyone.

The prognostic role of end of treatment FDG-PET-CT in patients with diffuse large B cell lymphoma can be improved by considering it with absolute monocyte count at diagnosis.

It is well established that some patients with diffuse large B-cell lymphoma (DLBCL) and the negative end of treatment PET-CT (EOT-PET-CT) will relapse, while a proportion with positive uptake can still obtain long-term EFS. We reviewed data of 200 consecutive, previously untreated patients with DLBCL recorded in Italy and Israel between 2007 and 2015. We found that patients with negative EOT-PET-CT with AMC > 630/mmc have a 3-years EFS of 72%, compared to those with AMC ≤ 630/mmc that have an EFS of 84%. Furthermore, considering patients with positive EOT-PET-CT, those with AMC > 630/mmc have a 3-years EFS of 8%, while those with AMC ≤ 630/mmc have an EFS of 38%. Thus, it appears that combining the gold standard for response evaluation EOT-PET-CT with a simple and inexpensive parameter like AMC at diagnosis, further improves prognostication in DLBCL. Applying this simple method can be useful for all doctors working in lymphoma clinical practice.

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

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.

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

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.

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).

Bendamustine, Low-dose dexamethasone, and lenalidomide (BdL) for the treatment of patients with relapsed/refractory multiple myeloma confirms very promising results in a phase I/II study.

Lenalidomide and dexamethasone are an effective treatment for naïve and relapsed multiple myeloma (MM) patients. Bendamustine is a good option for B-cell malignancies showing only partial cross resistance with alkylating agents used in MM patients. Based on these considerations, we proposed a phase I/II study testing escalating doses of bendamustine and lenalidomide and fixed low doses of dexamethasone (BdL). Fifteen patients were enrolled in phase I study. Maximum tolerated dose was established at dose "level 0": bendamustine 40 mg/m2 days 1,2; lenalidomide 10 mg days 1-21; d 40 mg days 1,8,15,22 every 28-day cycle, for six cycles. We enrolled 23 patients in the phase II study. BdL combination showed mainly hematological toxicities, fever and infections. Overall response rate was 47%. After median follow up of 22 months, median PFS was 10 months. Two-years OS rate was 65%. BdL combination confirmed to be a promising treatment for patients with relapsed/refractory MM.

Biological effects of Atra and Arsenic Trioxide on short term cultures of non-M3 leukemic blasts.

The efficacy of All-Trans Retinoic Acid (Atra) and Arsenic Trioxide (As(2)O(3)) in the treatment of Acute Promyelocytic Leukemia (APL) is well known. Further, these drugs inhibit cell growth and induce apoptosis in several cell lines, but few data are reported on leukemic blasts. The aim of this study was to evaluate the biological effects on non-M3 Acute Myeloid Leukemia (AML) cells. Blasts of six patients, after exposition to Atra and As(2)O(3) were tested for growth inhibition, induction of apoptosis and change in cell cycle distribution, evaluating cell viability, percentage of apoptotic cells and of blasts positive for Ki-67 and BrdU. In the present study we demonstrated that either Atra or As(2)O(3) inhibit leukemic cells proliferation by induction of apoptosis. The effects are time and dose dependent. We did not observe additive or synergistic effects with the combination of the drugs. Further, our results showed that Atra and As(2)O(3) have effects on cell cycle distribution reducing S-phase and proliferating cells. These results should be taken in to account preparing future laboratory and clinical experimental protocols that associate these drugs with antineoplastic agents with different cell cycle specificity.

Risk of Second Primary Malignancy in Breast Cancer Survivors: A Nested Population-Based Case-Control Study.

PURPOSE: Evolving therapies have improved the prognoses of patients with breast cancer; and currently, the number of long-term survivors is continuously increasing. However, these patients are at increased risk of developing a second cancer. Thus, late side effects are becoming an important issue. In this study, we aimed to investigate whether patient and tumor characteristics, and treatment type correlate with secondary tumor risk. METHODS: This case-control study included 305 patients with a diagnosed second malignancy after almost 6 months after the diagnosis of primary breast cancer and 1,525 controls (ratio 1:5 of cases to controls) from a population-based cohort of 6,325 women. The control patients were randomly selected from the cohort and matched to the cases according to age at diagnosis, calendar period of diagnosis, disease stage, and time of follow-up. RESULTS: BRCA1 or BRCA2 mutation, human epidermal growth factor receptor 2 (HER2)+ status, chemotherapy, and radiotherapy were related to increased risk of developing a second cancer, whereas hormonotherapy showed a protective effect. Chemotherapy, radiotherapy, and estrogenic receptor level <10% increased the risk of controlateral breast cancer. HER2+ status increased the risk of digestive system and thyroid tumors, while BRCA1 or BRCA2 mutation increased the risk of cancer in the genital system. CONCLUSION: Breast cancer survivors are exposed to an excess of risk of developing a second primary cancer. The development of excess of malignancies may be related either to patient and tumor characteristics, such as BRCA1 or BRCA2 mutation and HER2+ status, or to treatments factors.