A population-based cohort study on early-stage Hodgkin lymphoma treated with radiotherapy alone: with special reference to older patients

Background: Combined modality treatment has reduced the risk of relapse among younger early-stage Hodgkin lymphoma (HL) patients. Older HL patients may not tolerate chemotherapy and their prognosis is less favorable. We conducted a population-based study to evaluate long-term follow-up outcome in older early-stage HL patients initially treated with radiotherapy (RT) alone. Patients and methods: We included 308 consecutive patients (22% were ≥60 years) diagnosed 1972–1999 (median follow-up 20 years; range 1–28). Using Cox regression models we defined risk of relapse and survival in relation to clinical factors. Results: 272/308 (88%) patients obtained complete remission following first-line RT alone. Among these, 42% relapsed within a median of 21 months. The relapse rate was independent of gender and age at diagnosis (median age 32 years, range 14–85); however, lymphocyte-predominant HL was associated with borderline (P = 0.049) 56% decreased risk of relapse. Among patients <60 years and ≥60 years, we observed 29 (median latency 10 years, range 2–25) and 11 (median latency 3 years, range 1–10) second tumors, respectively. Conclusions: Older age (≥60 years) was not associated with an increased risk of relapse following RT alone. Given the risks of iatrogenic morbidity/mortality of chemotherapy in older patients, RT alone could be an alternative first-line therapy in early-stage older HL patients

High expression of cyclin B1 predicts a favorable outcome in patients with follicular lymphoma

Substantial research has been dedicated to the study of the relationship between genetic mechanisms regulating cell functions in tumors and how those tumors respond to various treatment regimens. Because these mechanisms are still not well understood, we have chosen to study the genetic makeup of 57 tumor samples from patients with follicular lymphoma (FL). Our goal was to develop a prognostic tool, which can be used as an aid in determining FL patients with tumors genetically predisposed to a successful treatment with the CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) regimen. To select relevant genes, high-density oligonucleotide arrays were used. There were 14 genes highly expressed in FL patients that responded well to CHOP chemotherapy, and 11 of these were involved in G(2)/M transition of the cell cycle, in mitosis, or in DNA modulation. A high expression of CCNB1 (cyclin B1), CDC2, CDKN3A, CKS1B, ANP32E, and KIAA0101, but not of the proliferation-related antigen Ki-67, was associated with better survival rate in a univariate analysis. CCNB1 expression had an independent prognostic value when included in a multivariate analysis together with the 5 parameters of the follicular lymphoma international prognostic index

Multiple Myeloma and Infections: A Population-Based Study Based On 9,610 Multiple Myeloma Patients

Abstract Abstract 945 Background Infections are a major cause of morbidity and mortality in patients with multiple myeloma (MM). No large population-based evaluation has been made to assess the risk of infections in MM patients compared to the normal population. Therefore, we performed a large study, using population-based data from Sweden, to estimate the risk of bacterial and viral infections among 9,610 MM patients compared to 37,718 matched controls. Methods We gathered information on all MM patients reported to the nationwide Swedish Cancer Registry from 1988 to 2004, with follow-up to 2007. For each MM patient, four population-based controls (matched by age, sex, and county of residence) were identified randomly from the Swedish population database. Information on occurrence and date of infections was obtained from the centralized Swedish Patient registry that captures information on individual patient-based discharge diagnosis from inpatient (with very high coverage) and outpatient care (since 2000). Cox proportional hazard models were used to estimate the overall, one- and five-year risk of infections. In addition, the effect of gender, age and calendar period of diagnosis was evaluated. Hazard ratios (HRs) and confidence intervals (CIs) were calculated for the occurrence of different infections. Results Overall, MM patients had a 6-fold (HR= 5.9; 95% CI=5.7-6.1) risk of developing any infection compared to matched controls (Figure). The increased risk of developing a bacterial infection was 6-fold (HR=5.9; 95%; CI=5.6-6.1), and for viral infections 9-fold (HR=9.0; 95% CI=8.0-10.1), compared to controls. More specifically, MM patients had an increased risk (p<0.05) of the following bacterial infections: cellulitis (HR=2.6; 95% CI =2.2-3.1), osteomyelitis (HR=3.0; 95% CI 2.0–4.4), endocarditis (HR=4.4; 95% CI 2.9–6.6), meningitis (HR=14.5; 95% CI 9.1–23.0), pneumonia (HR=6.2; 95% CI 5.9–6.5), pyelonephritis (HR=2.5; 95% CI 2.1–3.0), and septicaemia (HR=13.7; 95% CI 12.5–14.9) and for the viral infections influenza (HR=5.4; 95% CI 4.4–6.7) and herpes zoster (HR=12.8; 95% CI 10.5–15.5). The risk of infections was highest during the first year after diagnosis; the risk of bacterial infections was 11-fold (95% CI 10.7–12.9) and the risk of viral infections was 18-fold (95% CI 13.5–24.4) higher compared to controls during the first year after diagnosis. MM patients diagnosed in the more recent calendar periods had significantly higher risk of infections, reflected in a 1.6-fold (95% CI=1.5-1.7) and 2-fold (95% CI=1.9-2.1) increased risk in patients diagnosed during 1994–1999 and 2000–2004, compared to patients diagnosed 1986–1993. Females had a significantly lower risk of infections compared to males (p<0.001). Increasing age was significantly associated with a higher risk of infections (p<0.001). Discussion In this large population-based study including over 9,000 MM patients and 35,000 matched controls, we found that bacterial and viral infections represent a major threat to myeloma patients. We found the risk of specific infections like pneumonia, and septicemia to be over ten times higher in patients than in controls during the first year after MM diagnosis. Importantly, the risk of infections increased in more recent years. The effect on infectious complications due to novel drugs in the treatment of MM needs to be established and trials on prophylactic measures are required. Disclosures: Mellqvist: Janssen, Celgene: Honoraria

Monoclonal Gammopathy of Undetermined Significance and Risk of Infections A Population Based Study

Abstract Abstract 4053 Background: Based on clinical case reports and small hospital-based patient series, monoclonal gammopathy of undetermined significance (MGUS) has been reported to increase morbidity due to bacterial infections; however, no comprehensive evaluation has been conducted. Patients and methods: Using population-based data from Sweden, we assessed the risks of viral and bacterial infections (reported to the Patient-Registry) in 5,326 MGUS patients diagnosed 1958–2006, compared to 20,161 matched population-based controls. We fit Cox proportional hazard models to estimate hazard ratios (HRs) as measures of risk. Results: At 5 years of follow-up MGUS patients had a 2.1-fold (95% confidence interval (CI) 2.1–2.3) increased risk of developing any infection compared to controls; at 10 years of follow-up, the risk was very similar (HR=2.2; 95% CI 2.0–2.3). MGUS patients had a 2.2-fold (95% CI 2.0–2.4) and 2.1-fold (95% CI 2.0–2.3) increased risk of developing bacterial infections at 5 and 10 years, respectively. A significantly increased risk (P2.5 g/dL at diagnosis had higher risks of infections compared to those <0.5 g/dL. However, compared to controls the risk of infections was also significantly increased among MGUS patients with a concentration <0.5 g/dL. MGUS patients with (versus without) infections had no excess risk of developing multiple myeloma or related malignancies. Summary and Conclusions: Based on over 5,000 MGUS patients, we found a 2-fold higher risk of developing bacterial and viral infections, compared to controls. The risk was highest among MGUS patients with high M-protein concentrations at diagnosis (>2.5 g/dL); however, the risk was still significantly increased among those with a concentration <0.5 g/dL. Infections in patients with MGUS were not associated with an increased risk of malignant transformation. We recently showed that patients with MGUS have a 3-fold risk of death in bacterial infections. Our findings may have clinical implications for treatment strategies and prophylactic measures, as well as surveillance of MGUS patients. Disclosures: No relevant conflicts of interest to declare

Monoclonal Gammopathy of Undetermined Significance and Risk of Infections: A Population-Based Study

Abstract Abstract 4053 Background: Based on clinical case reports and small hospital-based patient series, monoclonal gammopathy of undetermined significance (MGUS) has been reported to increase morbidity due to bacterial infections; however, no comprehensive evaluation has been conducted. Patients and methods: Using population-based data from Sweden, we assessed the risks of viral and bacterial infections (reported to the Patient-Registry) in 5,326 MGUS patients diagnosed 1958–2006, compared to 20,161 matched population-based controls. We fit Cox proportional hazard models to estimate hazard ratios (HRs) as measures of risk. Results: At 5 years of follow-up MGUS patients had a 2.1-fold (95% confidence interval (CI) 2.1–2.3) increased risk of developing any infection compared to controls; at 10 years of follow-up, the risk was very similar (HR=2.2; 95% CI 2.0–2.3). MGUS patients had a 2.2-fold (95% CI 2.0–2.4) and 2.1-fold (95% CI 2.0–2.3) increased risk of developing bacterial infections at 5 and 10 years, respectively. A significantly increased risk (P2.5 g/dL at diagnosis had higher risks of infections compared to those <0.5 g/dL. However, compared to controls the risk of infections was also significantly increased among MGUS patients with a concentration <0.5 g/dL. MGUS patients with (versus without) infections had no excess risk of developing multiple myeloma or related malignancies. Summary and Conclusions: Based on over 5,000 MGUS patients, we found a 2-fold higher risk of developing bacterial and viral infections, compared to controls. The risk was highest among MGUS patients with high M-protein concentrations at diagnosis (>2.5 g/dL); however, the risk was still significantly increased among those with a concentration <0.5 g/dL. Infections in patients with MGUS were not associated with an increased risk of malignant transformation. We recently showed that patients with MGUS have a 3-fold risk of death in bacterial infections. Our findings may have clinical implications for treatment strategies and prophylactic measures, as well as surveillance of MGUS patients. Disclosures: No relevant conflicts of interest to declare

Risk and Cause of Death in 9,563 Patients Diagnosed with Myeloproliferative Neoplasms in Sweden Between 1973 and 2005

Abstract Abstract 3855 BACKGROUND The life expectancy of patients with myeloproliferative neoplasms (MPNs) is overall shorter than that of the general population. This is considered true for patients with polycythemia vera and primary myelofibrosis. A recent study by our group showed an inferior relative survival also for patients with essential thrombocythemia. Relative survival of MPN patients improved over the last decades but an excess mortality was observed among patients with all subtypes also during recent calendar periods. To elucidate the underlying causes of this excess mortality, we assessed the causes of death using a competing risk model in a large cohort of patients diagnosed with MPNs in Sweden 1973–2005 and compared the findings to those of matched controls. PATIENTS AND METHODS Patients were identified from the Swedish Cancer Registry and through our national MPN network. Matched controls without a hematological malignancy were identified through the Swedish Register of Total Population. Causes of death were identified using the Swedish Cause of Death Registry with follow-up until 2007. Cox regression was used to identify hazard ratios (HRs) with 95% confidence intervals (CIs) of dying from six different categories of death; infection, solid tumor, hematological malignancy, cardiovascular disease, cerebrovascular disease and other conditions. A competing risk analysis based on the Cox proportional hazards model was performed and results presented as stacked cumulative incidence plots. RESULTS We identified 9,563 MPN patients and their 37,643 controls. Forty-seven per cent of patients were males and the median age at diagnosis was 70 years. The distribution of cause specific deaths was similar for all MPN subtypes. The following results represent all MPN subtypes taken together. As expected, the probability of dying from any cause during the first 10 years after diagnosis was higher for cases compared to controls. For example, in MPN patients aged 70–79 at diagnosis the HR of dying from infection was 2.8 (CI 2.3–3.3), solid tumor HR=1.2 (1.1–1.4), hematological malignancy HR=∞, cardiovascular disease HR=1.5 (1.4–1.7), cerebrovascular disease HR=1.5 (1.3–1.8) and other disorders HR=2.1 (2.0–2.3). The probability of dying was higher in older persons and this age related effect was more pronounced in cases than controls. The overall mortality was very low in the youngest age group, so whilst in relative terms the risk of dying is far greater in the cases than the controls, in absolute terms the actual number of patients dying is quite small. For example the HR of dying from infections was 22.6 (8.4–60.8) and from cardiovascular disease HR=4.4 (2.8–7.0) in cases diagnosed between ages 18–49 years. In the competing risk model, studying male patients diagnosed between ages 70–79 during the calendar period 1993–2000 the overall probability of dying was 74% compared to 49% in controls within 10 years from diagnosis (Figure 1). The distribution of probabilities of cause specific death for cases and controls (within parenthesis) were infection 4.9% (2.4 %), solid tumors 9.9% (10.9%), hematological malignancy 13.4% (0.2%), cardiovascular disease 17.2% (15.3%), cerebrovascular disease 5.6% (5.0%) and other disorders 23.2% (15.1%) (Figure 1). The 10-year mortality rates decreased with calendar period for both cases and controls, both genders and for all age groups. The probability of dying from hematological malignancy in MPN patients remained the same over all calendar periods. The risk of cardiovascular death showed the largest decrease over time; however the decrease in risk was similar for both cases and controls (Figure 2). SUMMARY/CONCLUSIONS MPN patients in all subgroups had a higher probability of dying during the first 10 years after diagnosis compared to controls, mainly explained by death from a hematological malignancy. The major decrease in cardiovascular death in patients over the calendar periods is probability the main contributing factor to the improvement in 10-year survival. However, an almost identical trend was observed among controls suggesting a general improvement in the management of cardiovascular disease. Taken together the reason for the observed improvement in survival in MPN patients over time is probably multifactorial and is not only attributed to the management of the underlying hematological disorder per se. Studies elucidating contributing factors are ongoing. Disclosures: Björkholm: Shire: Research Funding